Key clinical point: Women who were diagnosed with breast cancer (BC) at a young age and underwent fertility preservation (FP) did not experience any increased risk for disease-specific mortality or relapse.

Major finding: Compared with women who did not undergo FP, disease-specific mortality was similar in women who underwent hormonal FP (adjusted hazard ratio [aHR] 0.59; 95% CI 0.32-1.09) and nonhormonal FP (aHR 0.51; 95% CI 0.20-1.29). Hormonal (aHR 0.81; 95% CI 0.49-1.37) and nonhormonal (aHR 0.75; 95% CI 0.35-1.62) FP were associated with similar relapse or death rates in a subcohort of 723 women with complete relapse information.

Study details: Findings are from an analysis of a population-based nationwide cohort study including 1275 women of reproductive age (18-44 years old) who were diagnosed with BC, of which 425 women received hormonal (n = 367) or nonhormonal (n = 58) FP treatment.

Disclosures: This study was supported by the Swedish Cancer Society and other sources. Prof. Bergh declared receiving grants and personal fees from several sources.

Source: Marklund A et al. Relapse rates and disease-specific mortality following procedures for fertility preservation at time of breast cancer diagnosis. JAMA Oncol. 2022 (Aug 25). Doi: 10.1001/jamaoncol.2022.3677

Key clinical point: Women who were diagnosed with breast cancer (BC) at a young age and underwent fertility preservation (FP) did not experience any increased risk for disease-specific mortality or relapse.

Major finding: Compared with women who did not undergo FP, disease-specific mortality was similar in women who underwent hormonal FP (adjusted hazard ratio [aHR] 0.59; 95% CI 0.32-1.09) and nonhormonal FP (aHR 0.51; 95% CI 0.20-1.29). Hormonal (aHR 0.81; 95% CI 0.49-1.37) and nonhormonal (aHR 0.75; 95% CI 0.35-1.62) FP were associated with similar relapse or death rates in a subcohort of 723 women with complete relapse information.

Study details: Findings are from an analysis of a population-based nationwide cohort study including 1275 women of reproductive age (18-44 years old) who were diagnosed with BC, of which 425 women received hormonal (n = 367) or nonhormonal (n = 58) FP treatment.

Disclosures: This study was supported by the Swedish Cancer Society and other sources. Prof. Bergh declared receiving grants and personal fees from several sources.

Source: Marklund A et al. Relapse rates and disease-specific mortality following procedures for fertility preservation at time of breast cancer diagnosis. JAMA Oncol. 2022 (Aug 25). Doi: 10.1001/jamaoncol.2022.3677

Key clinical point: Women who were diagnosed with breast cancer (BC) at a young age and underwent fertility preservation (FP) did not experience any increased risk for disease-specific mortality or relapse.

Major finding: Compared with women who did not undergo FP, disease-specific mortality was similar in women who underwent hormonal FP (adjusted hazard ratio [aHR] 0.59; 95% CI 0.32-1.09) and nonhormonal FP (aHR 0.51; 95% CI 0.20-1.29). Hormonal (aHR 0.81; 95% CI 0.49-1.37) and nonhormonal (aHR 0.75; 95% CI 0.35-1.62) FP were associated with similar relapse or death rates in a subcohort of 723 women with complete relapse information.

Study details: Findings are from an analysis of a population-based nationwide cohort study including 1275 women of reproductive age (18-44 years old) who were diagnosed with BC, of which 425 women received hormonal (n = 367) or nonhormonal (n = 58) FP treatment.

Disclosures: This study was supported by the Swedish Cancer Society and other sources. Prof. Bergh declared receiving grants and personal fees from several sources.

Source: Marklund A et al. Relapse rates and disease-specific mortality following procedures for fertility preservation at time of breast cancer diagnosis. JAMA Oncol. 2022 (Aug 25). Doi: 10.1001/jamaoncol.2022.3677

Key clinical point: In estrogen receptor-positive/human epidermal growth factor receptor-positive (ER+/HER2+) breast cancer (BC), HER2-enriched (HER2-E) tumors were more likely to respond poorly to aromatase inhibitor (AI) therapy and pose an increased risk for disease recurrence.

Major finding: AI-treated HER2-E tumors were associated with poorer Ki67 response and higher Ki67 expression level at 2-weeks timepoint compared with luminal A and B tumors (odds ratio 1.52-12.31; false discovery rate < 0.0001). HER2-E subtype was an independent predictor of shorter time to recurrence (hazard ratio 2.55; P   =   .022).

Study details: Findings are from the phase 3 POETIC trial including 342 patients with early ER+/HER2+ BC who were assigned to 2 weeks of perisurgical AI (n = 237) or no AI (n = 105).

Disclosures: This study was funded by Cancer Research UK. Some authors declared holding or filing patents or receiving grants, nonfinancial support, consulting fees, honoraria, or research funding from several sources.

Source: Bergamino MA et al. HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer. EBioMedicine. 2022;83:104205 (Aug 16). Doi: 10.1016/j.ebiom.2022.104205

Key clinical point: In estrogen receptor-positive/human epidermal growth factor receptor-positive (ER+/HER2+) breast cancer (BC), HER2-enriched (HER2-E) tumors were more likely to respond poorly to aromatase inhibitor (AI) therapy and pose an increased risk for disease recurrence.

Major finding: AI-treated HER2-E tumors were associated with poorer Ki67 response and higher Ki67 expression level at 2-weeks timepoint compared with luminal A and B tumors (odds ratio 1.52-12.31; false discovery rate < 0.0001). HER2-E subtype was an independent predictor of shorter time to recurrence (hazard ratio 2.55; P   =   .022).

Study details: Findings are from the phase 3 POETIC trial including 342 patients with early ER+/HER2+ BC who were assigned to 2 weeks of perisurgical AI (n = 237) or no AI (n = 105).

Disclosures: This study was funded by Cancer Research UK. Some authors declared holding or filing patents or receiving grants, nonfinancial support, consulting fees, honoraria, or research funding from several sources.

Source: Bergamino MA et al. HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer. EBioMedicine. 2022;83:104205 (Aug 16). Doi: 10.1016/j.ebiom.2022.104205

Key clinical point: In estrogen receptor-positive/human epidermal growth factor receptor-positive (ER+/HER2+) breast cancer (BC), HER2-enriched (HER2-E) tumors were more likely to respond poorly to aromatase inhibitor (AI) therapy and pose an increased risk for disease recurrence.

Major finding: AI-treated HER2-E tumors were associated with poorer Ki67 response and higher Ki67 expression level at 2-weeks timepoint compared with luminal A and B tumors (odds ratio 1.52-12.31; false discovery rate < 0.0001). HER2-E subtype was an independent predictor of shorter time to recurrence (hazard ratio 2.55; P   =   .022).

Study details: Findings are from the phase 3 POETIC trial including 342 patients with early ER+/HER2+ BC who were assigned to 2 weeks of perisurgical AI (n = 237) or no AI (n = 105).

Disclosures: This study was funded by Cancer Research UK. Some authors declared holding or filing patents or receiving grants, nonfinancial support, consulting fees, honoraria, or research funding from several sources.

Source: Bergamino MA et al. HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer. EBioMedicine. 2022;83:104205 (Aug 16). Doi: 10.1016/j.ebiom.2022.104205

Key clinical point: Patients with human epidermal growth factor receptor 2-positive (ERBB2+) and triple-negative breast cancer (TNBC) are more likely to need radiation for brain metastasis (BRM) than those with other BC subtypes.

Major finding: At the 3-year timepoint, the cumulative incidences of BRM was highest in patients with ERBB2+/hormone receptor-negative (HR−) BC (25.3%). TNBC (hazard ratio 4.25), ERBB2+/HR+ BC (hazard ratio 1.94), and ERBB2+/HR− BC (hazard ratio 2.81; all P < .001) were associated with a shorter time from BC diagnosis to brain radiotherapy than HR+/ERBB2− BC. Patients who received radiotherapy for BRM were more likely to have TNBC or ERBB2+ BC than HR+/ERBB2− BC (P < .001).

Study details: Findings are from a retrospective, observational population-based cohort study including 3916 patients with metastatic BC, of which 31.0% had HR+/ERBB2− BC, 7.9% had ERBB2+/HR+ BC, 5.1% had ERBB2+/HR− BC, and 6.6% had TNBC.

Disclosures: This research was supported by Eli Lilly. Some authors declared serving as consultants, board members, or speakers or receiving grants or personal fees from several sources, including Eli Lilly.

Source: Wang XY et al. Analysis of rates of brain metastases and association with breast cancer subtypes in Ontario, Canada. JAMA Netw Open. 2022;5(8):e2225424 (Aug 12). Doi: 10.1001/jamanetworkopen.2022.25424

Key clinical point: Patients with human epidermal growth factor receptor 2-positive (ERBB2+) and triple-negative breast cancer (TNBC) are more likely to need radiation for brain metastasis (BRM) than those with other BC subtypes.

Major finding: At the 3-year timepoint, the cumulative incidences of BRM was highest in patients with ERBB2+/hormone receptor-negative (HR−) BC (25.3%). TNBC (hazard ratio 4.25), ERBB2+/HR+ BC (hazard ratio 1.94), and ERBB2+/HR− BC (hazard ratio 2.81; all P < .001) were associated with a shorter time from BC diagnosis to brain radiotherapy than HR+/ERBB2− BC. Patients who received radiotherapy for BRM were more likely to have TNBC or ERBB2+ BC than HR+/ERBB2− BC (P < .001).

Study details: Findings are from a retrospective, observational population-based cohort study including 3916 patients with metastatic BC, of which 31.0% had HR+/ERBB2− BC, 7.9% had ERBB2+/HR+ BC, 5.1% had ERBB2+/HR− BC, and 6.6% had TNBC.

Disclosures: This research was supported by Eli Lilly. Some authors declared serving as consultants, board members, or speakers or receiving grants or personal fees from several sources, including Eli Lilly.

Source: Wang XY et al. Analysis of rates of brain metastases and association with breast cancer subtypes in Ontario, Canada. JAMA Netw Open. 2022;5(8):e2225424 (Aug 12). Doi: 10.1001/jamanetworkopen.2022.25424

Key clinical point: Patients with human epidermal growth factor receptor 2-positive (ERBB2+) and triple-negative breast cancer (TNBC) are more likely to need radiation for brain metastasis (BRM) than those with other BC subtypes.

Major finding: At the 3-year timepoint, the cumulative incidences of BRM was highest in patients with ERBB2+/hormone receptor-negative (HR−) BC (25.3%). TNBC (hazard ratio 4.25), ERBB2+/HR+ BC (hazard ratio 1.94), and ERBB2+/HR− BC (hazard ratio 2.81; all P < .001) were associated with a shorter time from BC diagnosis to brain radiotherapy than HR+/ERBB2− BC. Patients who received radiotherapy for BRM were more likely to have TNBC or ERBB2+ BC than HR+/ERBB2− BC (P < .001).

Study details: Findings are from a retrospective, observational population-based cohort study including 3916 patients with metastatic BC, of which 31.0% had HR+/ERBB2− BC, 7.9% had ERBB2+/HR+ BC, 5.1% had ERBB2+/HR− BC, and 6.6% had TNBC.

Disclosures: This research was supported by Eli Lilly. Some authors declared serving as consultants, board members, or speakers or receiving grants or personal fees from several sources, including Eli Lilly.

Source: Wang XY et al. Analysis of rates of brain metastases and association with breast cancer subtypes in Ontario, Canada. JAMA Netw Open. 2022;5(8):e2225424 (Aug 12). Doi: 10.1001/jamanetworkopen.2022.25424

Additional hidradenitis suppurativa (HS) treatments could be on the horizon with the news that both secukinumab and the investigational drug brepocitinib reduced the effects of the chronic and painful skin condition in separate trials.

Around 40%-50% of patients exhibited a clinical response to these agents at 16 weeks, a leading HS expert reported at the annual congress of the European Academy of Dermatology and Venereology.
 

Time in the spotlight for HS

Research into HS is “an incredibly active field at this moment,” said Alexa B. Kimball, MD, MPH, professor of dermatology, Harvard Medical School, and president and chief executive officer of Harvard Medical Faculty Physicians at Beth Israel Deaconess Medical Center, Boston.

It’s “been great for advancing our understanding of the biology and the treatments that we will be able to use,” she said.

During the late-breaking sessions at the annual EADV Congress, Dr. Kimball presented data from two trials – SUNSHINE and SUNRISE – that investigated the efficacy, safety and tolerability of the interleukin (IL) 17A inhibitor secukinumab (Cosentyx) versus placebo in the treatment of moderate to severe HS.

“This is only the second phase 3 program we have ever seen in HS and the first one since 2016,” Dr. Kimball said of the trials. It’s also the largest trial program in HS conducted to date, she added, “so it really is a milestone.”

The last big development was when adalimumab, a tumor necrosis factor (TNF) blocker, gained regulatory approval for HS in 2016, observed Neil Patel, PhD, MRCP, who leads the HS service at Imperial College Healthcare NHS Trust in London.

“Adalimumab has been very helpful for many patients, but not all patients respond, and others may respond initially but then the treatment starts to fail after a year or 2,” Dr. Patel said in an interview with this news organization.

“There is definitely a huge need for alternative medication for this condition, which still has a lack of effective treatment options,” added Dr. Patel, who was not involved in either of the studies.

“One major upside for secukinumab is that its safety profile is generally very good and familiarity in the dermatologic community is already well established,” Christopher Sayed, MD, said in a separate interview.

“This will make most providers very comfortable offering it as a potential treatment option sooner rather than later given that its efficacy has now been demonstrated in phase 3 trials,” added Dr. Sayed, associate professor of dermatology at the University of North Carolina at Chapel Hill.
 

Two identically designed trials

Altogether, SUNSHINE and SUNRISE enrolled just over 1,000 patients at 219 sites in 33 countries. Both trials were identical in their design: A 4-week run-in phase before a randomized, double-blind treatment phase that tested two dosing regimens of secukinumab (300 mg administered subcutaneously) every 2 or 4 weeks vs. placebo for 16 weeks. The trial continued after this time, with patients in the placebo arm re–randomly assigned to treatment with one of the two secukinumab regimens out to a year.

The primary endpoint was the percentage of patients achieving a Hidradenitis Suppurativa Clinical Response (HiSCR) after 16 weeks of treatment, with key secondary endpoints, which were abscess and inflammatory nodule (AN) count, occurrence of flares, and at least a 30% reduction in Patient’s Global Assessment of Skin Pain assessed using a numeric rating scale (NPRS30).
 

Secukinumab superior to placebo

The HiSCR is defined as at least a 50% decrease in AN count with no increase in the number of abscesses or in the number of draining fistulas relative to baseline. This was achieved by about 42%-45% of patients who received secukinumab every 2 weeks, about 42%-46% of those who received secukinumab every 4 weeks, and about 31%-33% of those on placebo in both studies.

Of note, fewer patients treated with secukinumab (about 15%-20% among those treated every 2 weeks, and about 15% to 23% among those treated every 4 weeks) than those on placebo (27%-29%) experienced flares, defined as at least a 25% increase in AN count and at least a two-point increase relative to baseline values.

Improvement in HS pain can be a difficult parameter to meet, Dr. Kimball noted. “Pain is such an important feature of this disease as it so debilitating for the patients.” More than one-third (almost 36%-39%) of patients given secukinumab vs. just over a quarter (26.9%) given placebo achieved at least a 30% reduction in NPRS30 ratings, she reported. The difference between active and placebo treatment was significant only when secukinumab was given every 2 weeks, however.

“The placebo rates that we see in these studies are exactly parallel to what we saw in other studies, and other disease states when we had a 50% bar of improvement,” Dr. Kimball said when questioned about these results.

“HS is a highly variable disease; it’s maybe not so much the placebo rate or the scoring system used but maybe the 50% bar set for improvement is too low. It’s likely, as data start to mature and a 75% HiSCR can be calculated, that the placebo rates will drop,” she said.

There were no surprises when it came to the safety of secukinumab, being an old player in a new game, she noted. It was “well tolerated” and tolerability was “consistent with the known safety profile,” Dr. Kimball said, “so we expect it to be a new, safe, and effective add to our armamentarium in treating this disease.”

This research involves “basically borrowing drugs from other areas and trying them in HS to see what effect they may have,” Dr. Patel said, noting that drugs such as adalimumab and secukinumab already had a proven track record in other diseases, such as psoriasis. “These early data for secukinumab definitely are very exciting, but we would need to see real-life results” in patients with HS who are not enrolled in trials to see the benefits, he added.

‘Tipping point’ for HS research

“I think we will look back on this meeting and realize that it was an incredibly important tipping point for the treatment of this incredibly debilitating disease,” Dr. Kimball said.

Elsewhere at the meeting, she had presented findings from a phase 2a study that pitted three different kinase inhibitors with different modes of action against each other and compared them with placebo. 

The three agents evaluated are an IL-1 receptor–associated kinase 4 inhibitor known as PF-06650833, a tyrosine kinase 2 (TYK2) JAK1 inhibitor brepocitinib, and the TYK2 inhibitor PF-06826647.

“This technique has been used in oncology,” Dr. Kimball said, noting that the ability to test multiple drugs at the same time “means we can really much more efficiently test two different things at the same time, and also put fewer patients at risk for potential problems if drugs don’t work.”
 

Positive signs for brepocitinib, not the other kinases tested

The results showed that though brepocitinib worked in HS, the other two novel compounds did not appear to have beneficial effects. Just over half (52%) of the 52 patients treated with brepocitinib achieved an HiSCR at 16 weeks, compared with around one-third of those given placebo, PF-06650833, or PF-06826647.

A similar benefit was seen in terms of reduction in flares for brepocitinib but not the other agents, although there was no difference between them all in terms of NPRS30 pain reduction.

“We’ve been able to test three different modalities. This tells us some things about the pathophysiology for HS, which is a very profoundly intensive inflammatory process,” which, Dr. Kimball said, “may require multiple modalities of action to get it under control.” In addition, these “general modalities seem to safe and well tolerated,” she added.
 

Take-homes for practice and future research

“While it is disappointing that two of the drugs tested did not clearly demonstrate efficacy, it is very possible that these mechanisms of action may be successful targets in the future as new dosing strategies and drugs targeting these pathways are developed,” Dr. Sayed said.

A case in point, he added, was that “adalimumab did not meet treatment endpoints at a dose of 40 mg every other week, but clearly has made a major impact at 40 mg weekly.”

The bottom line is that “both secukinumab and beprocitinib demonstrated efficacy over placebo and are likely to be helpful for a significant number of patients with HS,” Dr. Sayed said. “Hopefully, we’ll see head-to-head trials and more data regarding proportions of patients with deeper responses using criteria such as HiSCR75 and HiSCR90.”

Moreover, “having a larger number of drugs with a range of mechanisms of action is extraordinarily helpful given how difficult the disease can be to manage. We will hopefully continue to see creative approaches and further successes in the current wave of phase 1, 2, and 3 trials that are already underway.”

The SUNSHINE and SUNRISE studies were funded by Novartis Pharma AG, Basel, Switzerland. The phase 2A study Dr. Kimball presented was sponsored by Pfizer.

Dr. Kimball disclosed ties to both Novartis and Pfizer and acts as a consultant and investigator to AbbVie, Bristol-Myers Squibb, Janssen, Eli Lilly, Novartis, and UCB. She is an investigator for Incyte and AnaptysBio; acts as a consultant to Bayer, Boehringer Ingelheim, Ventyz, Moonlake, Lily, Concert, EvoImmune, Sonoma Bio, and Sanofi; receives fellowship funding from Janssen, and serves on the Board of Directors for Almirall.

Dr. Patel had no conflicts of interest to disclose. Dr. Sayed is the director of the HS Foundation, a nonprofit organization, and has acted as an adviser or consultant to, speaker for, and received research funding from multiple drug companies including AbbVie, ChemoCentryx, Incyte, InflaRx, Novartis, and UCB.

A version of this article first appeared on Medscape.com.

Additional hidradenitis suppurativa (HS) treatments could be on the horizon with the news that both secukinumab and the investigational drug brepocitinib reduced the effects of the chronic and painful skin condition in separate trials.

Around 40%-50% of patients exhibited a clinical response to these agents at 16 weeks, a leading HS expert reported at the annual congress of the European Academy of Dermatology and Venereology.
 

Time in the spotlight for HS

Research into HS is “an incredibly active field at this moment,” said Alexa B. Kimball, MD, MPH, professor of dermatology, Harvard Medical School, and president and chief executive officer of Harvard Medical Faculty Physicians at Beth Israel Deaconess Medical Center, Boston.

It’s “been great for advancing our understanding of the biology and the treatments that we will be able to use,” she said.

During the late-breaking sessions at the annual EADV Congress, Dr. Kimball presented data from two trials – SUNSHINE and SUNRISE – that investigated the efficacy, safety and tolerability of the interleukin (IL) 17A inhibitor secukinumab (Cosentyx) versus placebo in the treatment of moderate to severe HS.

“This is only the second phase 3 program we have ever seen in HS and the first one since 2016,” Dr. Kimball said of the trials. It’s also the largest trial program in HS conducted to date, she added, “so it really is a milestone.”

The last big development was when adalimumab, a tumor necrosis factor (TNF) blocker, gained regulatory approval for HS in 2016, observed Neil Patel, PhD, MRCP, who leads the HS service at Imperial College Healthcare NHS Trust in London.

“Adalimumab has been very helpful for many patients, but not all patients respond, and others may respond initially but then the treatment starts to fail after a year or 2,” Dr. Patel said in an interview with this news organization.

“There is definitely a huge need for alternative medication for this condition, which still has a lack of effective treatment options,” added Dr. Patel, who was not involved in either of the studies.

“One major upside for secukinumab is that its safety profile is generally very good and familiarity in the dermatologic community is already well established,” Christopher Sayed, MD, said in a separate interview.

“This will make most providers very comfortable offering it as a potential treatment option sooner rather than later given that its efficacy has now been demonstrated in phase 3 trials,” added Dr. Sayed, associate professor of dermatology at the University of North Carolina at Chapel Hill.
 

Two identically designed trials

Altogether, SUNSHINE and SUNRISE enrolled just over 1,000 patients at 219 sites in 33 countries. Both trials were identical in their design: A 4-week run-in phase before a randomized, double-blind treatment phase that tested two dosing regimens of secukinumab (300 mg administered subcutaneously) every 2 or 4 weeks vs. placebo for 16 weeks. The trial continued after this time, with patients in the placebo arm re–randomly assigned to treatment with one of the two secukinumab regimens out to a year.

The primary endpoint was the percentage of patients achieving a Hidradenitis Suppurativa Clinical Response (HiSCR) after 16 weeks of treatment, with key secondary endpoints, which were abscess and inflammatory nodule (AN) count, occurrence of flares, and at least a 30% reduction in Patient’s Global Assessment of Skin Pain assessed using a numeric rating scale (NPRS30).
 

Secukinumab superior to placebo

The HiSCR is defined as at least a 50% decrease in AN count with no increase in the number of abscesses or in the number of draining fistulas relative to baseline. This was achieved by about 42%-45% of patients who received secukinumab every 2 weeks, about 42%-46% of those who received secukinumab every 4 weeks, and about 31%-33% of those on placebo in both studies.

Of note, fewer patients treated with secukinumab (about 15%-20% among those treated every 2 weeks, and about 15% to 23% among those treated every 4 weeks) than those on placebo (27%-29%) experienced flares, defined as at least a 25% increase in AN count and at least a two-point increase relative to baseline values.

Improvement in HS pain can be a difficult parameter to meet, Dr. Kimball noted. “Pain is such an important feature of this disease as it so debilitating for the patients.” More than one-third (almost 36%-39%) of patients given secukinumab vs. just over a quarter (26.9%) given placebo achieved at least a 30% reduction in NPRS30 ratings, she reported. The difference between active and placebo treatment was significant only when secukinumab was given every 2 weeks, however.

“The placebo rates that we see in these studies are exactly parallel to what we saw in other studies, and other disease states when we had a 50% bar of improvement,” Dr. Kimball said when questioned about these results.

“HS is a highly variable disease; it’s maybe not so much the placebo rate or the scoring system used but maybe the 50% bar set for improvement is too low. It’s likely, as data start to mature and a 75% HiSCR can be calculated, that the placebo rates will drop,” she said.

There were no surprises when it came to the safety of secukinumab, being an old player in a new game, she noted. It was “well tolerated” and tolerability was “consistent with the known safety profile,” Dr. Kimball said, “so we expect it to be a new, safe, and effective add to our armamentarium in treating this disease.”

This research involves “basically borrowing drugs from other areas and trying them in HS to see what effect they may have,” Dr. Patel said, noting that drugs such as adalimumab and secukinumab already had a proven track record in other diseases, such as psoriasis. “These early data for secukinumab definitely are very exciting, but we would need to see real-life results” in patients with HS who are not enrolled in trials to see the benefits, he added.

‘Tipping point’ for HS research

“I think we will look back on this meeting and realize that it was an incredibly important tipping point for the treatment of this incredibly debilitating disease,” Dr. Kimball said.

Elsewhere at the meeting, she had presented findings from a phase 2a study that pitted three different kinase inhibitors with different modes of action against each other and compared them with placebo. 

The three agents evaluated are an IL-1 receptor–associated kinase 4 inhibitor known as PF-06650833, a tyrosine kinase 2 (TYK2) JAK1 inhibitor brepocitinib, and the TYK2 inhibitor PF-06826647.

“This technique has been used in oncology,” Dr. Kimball said, noting that the ability to test multiple drugs at the same time “means we can really much more efficiently test two different things at the same time, and also put fewer patients at risk for potential problems if drugs don’t work.”
 

Positive signs for brepocitinib, not the other kinases tested

The results showed that though brepocitinib worked in HS, the other two novel compounds did not appear to have beneficial effects. Just over half (52%) of the 52 patients treated with brepocitinib achieved an HiSCR at 16 weeks, compared with around one-third of those given placebo, PF-06650833, or PF-06826647.

A similar benefit was seen in terms of reduction in flares for brepocitinib but not the other agents, although there was no difference between them all in terms of NPRS30 pain reduction.

“We’ve been able to test three different modalities. This tells us some things about the pathophysiology for HS, which is a very profoundly intensive inflammatory process,” which, Dr. Kimball said, “may require multiple modalities of action to get it under control.” In addition, these “general modalities seem to safe and well tolerated,” she added.
 

Take-homes for practice and future research

“While it is disappointing that two of the drugs tested did not clearly demonstrate efficacy, it is very possible that these mechanisms of action may be successful targets in the future as new dosing strategies and drugs targeting these pathways are developed,” Dr. Sayed said.

A case in point, he added, was that “adalimumab did not meet treatment endpoints at a dose of 40 mg every other week, but clearly has made a major impact at 40 mg weekly.”

The bottom line is that “both secukinumab and beprocitinib demonstrated efficacy over placebo and are likely to be helpful for a significant number of patients with HS,” Dr. Sayed said. “Hopefully, we’ll see head-to-head trials and more data regarding proportions of patients with deeper responses using criteria such as HiSCR75 and HiSCR90.”

Moreover, “having a larger number of drugs with a range of mechanisms of action is extraordinarily helpful given how difficult the disease can be to manage. We will hopefully continue to see creative approaches and further successes in the current wave of phase 1, 2, and 3 trials that are already underway.”

The SUNSHINE and SUNRISE studies were funded by Novartis Pharma AG, Basel, Switzerland. The phase 2A study Dr. Kimball presented was sponsored by Pfizer.

Dr. Kimball disclosed ties to both Novartis and Pfizer and acts as a consultant and investigator to AbbVie, Bristol-Myers Squibb, Janssen, Eli Lilly, Novartis, and UCB. She is an investigator for Incyte and AnaptysBio; acts as a consultant to Bayer, Boehringer Ingelheim, Ventyz, Moonlake, Lily, Concert, EvoImmune, Sonoma Bio, and Sanofi; receives fellowship funding from Janssen, and serves on the Board of Directors for Almirall.

Dr. Patel had no conflicts of interest to disclose. Dr. Sayed is the director of the HS Foundation, a nonprofit organization, and has acted as an adviser or consultant to, speaker for, and received research funding from multiple drug companies including AbbVie, ChemoCentryx, Incyte, InflaRx, Novartis, and UCB.

A version of this article first appeared on Medscape.com.

Additional hidradenitis suppurativa (HS) treatments could be on the horizon with the news that both secukinumab and the investigational drug brepocitinib reduced the effects of the chronic and painful skin condition in separate trials.

Around 40%-50% of patients exhibited a clinical response to these agents at 16 weeks, a leading HS expert reported at the annual congress of the European Academy of Dermatology and Venereology.
 

Time in the spotlight for HS

Research into HS is “an incredibly active field at this moment,” said Alexa B. Kimball, MD, MPH, professor of dermatology, Harvard Medical School, and president and chief executive officer of Harvard Medical Faculty Physicians at Beth Israel Deaconess Medical Center, Boston.

It’s “been great for advancing our understanding of the biology and the treatments that we will be able to use,” she said.

During the late-breaking sessions at the annual EADV Congress, Dr. Kimball presented data from two trials – SUNSHINE and SUNRISE – that investigated the efficacy, safety and tolerability of the interleukin (IL) 17A inhibitor secukinumab (Cosentyx) versus placebo in the treatment of moderate to severe HS.

“This is only the second phase 3 program we have ever seen in HS and the first one since 2016,” Dr. Kimball said of the trials. It’s also the largest trial program in HS conducted to date, she added, “so it really is a milestone.”

The last big development was when adalimumab, a tumor necrosis factor (TNF) blocker, gained regulatory approval for HS in 2016, observed Neil Patel, PhD, MRCP, who leads the HS service at Imperial College Healthcare NHS Trust in London.

“Adalimumab has been very helpful for many patients, but not all patients respond, and others may respond initially but then the treatment starts to fail after a year or 2,” Dr. Patel said in an interview with this news organization.

“There is definitely a huge need for alternative medication for this condition, which still has a lack of effective treatment options,” added Dr. Patel, who was not involved in either of the studies.

“One major upside for secukinumab is that its safety profile is generally very good and familiarity in the dermatologic community is already well established,” Christopher Sayed, MD, said in a separate interview.

“This will make most providers very comfortable offering it as a potential treatment option sooner rather than later given that its efficacy has now been demonstrated in phase 3 trials,” added Dr. Sayed, associate professor of dermatology at the University of North Carolina at Chapel Hill.
 

Two identically designed trials

Altogether, SUNSHINE and SUNRISE enrolled just over 1,000 patients at 219 sites in 33 countries. Both trials were identical in their design: A 4-week run-in phase before a randomized, double-blind treatment phase that tested two dosing regimens of secukinumab (300 mg administered subcutaneously) every 2 or 4 weeks vs. placebo for 16 weeks. The trial continued after this time, with patients in the placebo arm re–randomly assigned to treatment with one of the two secukinumab regimens out to a year.

The primary endpoint was the percentage of patients achieving a Hidradenitis Suppurativa Clinical Response (HiSCR) after 16 weeks of treatment, with key secondary endpoints, which were abscess and inflammatory nodule (AN) count, occurrence of flares, and at least a 30% reduction in Patient’s Global Assessment of Skin Pain assessed using a numeric rating scale (NPRS30).
 

Secukinumab superior to placebo

The HiSCR is defined as at least a 50% decrease in AN count with no increase in the number of abscesses or in the number of draining fistulas relative to baseline. This was achieved by about 42%-45% of patients who received secukinumab every 2 weeks, about 42%-46% of those who received secukinumab every 4 weeks, and about 31%-33% of those on placebo in both studies.

Of note, fewer patients treated with secukinumab (about 15%-20% among those treated every 2 weeks, and about 15% to 23% among those treated every 4 weeks) than those on placebo (27%-29%) experienced flares, defined as at least a 25% increase in AN count and at least a two-point increase relative to baseline values.

Improvement in HS pain can be a difficult parameter to meet, Dr. Kimball noted. “Pain is such an important feature of this disease as it so debilitating for the patients.” More than one-third (almost 36%-39%) of patients given secukinumab vs. just over a quarter (26.9%) given placebo achieved at least a 30% reduction in NPRS30 ratings, she reported. The difference between active and placebo treatment was significant only when secukinumab was given every 2 weeks, however.

“The placebo rates that we see in these studies are exactly parallel to what we saw in other studies, and other disease states when we had a 50% bar of improvement,” Dr. Kimball said when questioned about these results.

“HS is a highly variable disease; it’s maybe not so much the placebo rate or the scoring system used but maybe the 50% bar set for improvement is too low. It’s likely, as data start to mature and a 75% HiSCR can be calculated, that the placebo rates will drop,” she said.

There were no surprises when it came to the safety of secukinumab, being an old player in a new game, she noted. It was “well tolerated” and tolerability was “consistent with the known safety profile,” Dr. Kimball said, “so we expect it to be a new, safe, and effective add to our armamentarium in treating this disease.”

This research involves “basically borrowing drugs from other areas and trying them in HS to see what effect they may have,” Dr. Patel said, noting that drugs such as adalimumab and secukinumab already had a proven track record in other diseases, such as psoriasis. “These early data for secukinumab definitely are very exciting, but we would need to see real-life results” in patients with HS who are not enrolled in trials to see the benefits, he added.

‘Tipping point’ for HS research

“I think we will look back on this meeting and realize that it was an incredibly important tipping point for the treatment of this incredibly debilitating disease,” Dr. Kimball said.

Elsewhere at the meeting, she had presented findings from a phase 2a study that pitted three different kinase inhibitors with different modes of action against each other and compared them with placebo. 

The three agents evaluated are an IL-1 receptor–associated kinase 4 inhibitor known as PF-06650833, a tyrosine kinase 2 (TYK2) JAK1 inhibitor brepocitinib, and the TYK2 inhibitor PF-06826647.

“This technique has been used in oncology,” Dr. Kimball said, noting that the ability to test multiple drugs at the same time “means we can really much more efficiently test two different things at the same time, and also put fewer patients at risk for potential problems if drugs don’t work.”
 

Positive signs for brepocitinib, not the other kinases tested

The results showed that though brepocitinib worked in HS, the other two novel compounds did not appear to have beneficial effects. Just over half (52%) of the 52 patients treated with brepocitinib achieved an HiSCR at 16 weeks, compared with around one-third of those given placebo, PF-06650833, or PF-06826647.

A similar benefit was seen in terms of reduction in flares for brepocitinib but not the other agents, although there was no difference between them all in terms of NPRS30 pain reduction.

“We’ve been able to test three different modalities. This tells us some things about the pathophysiology for HS, which is a very profoundly intensive inflammatory process,” which, Dr. Kimball said, “may require multiple modalities of action to get it under control.” In addition, these “general modalities seem to safe and well tolerated,” she added.
 

Take-homes for practice and future research

“While it is disappointing that two of the drugs tested did not clearly demonstrate efficacy, it is very possible that these mechanisms of action may be successful targets in the future as new dosing strategies and drugs targeting these pathways are developed,” Dr. Sayed said.

A case in point, he added, was that “adalimumab did not meet treatment endpoints at a dose of 40 mg every other week, but clearly has made a major impact at 40 mg weekly.”

The bottom line is that “both secukinumab and beprocitinib demonstrated efficacy over placebo and are likely to be helpful for a significant number of patients with HS,” Dr. Sayed said. “Hopefully, we’ll see head-to-head trials and more data regarding proportions of patients with deeper responses using criteria such as HiSCR75 and HiSCR90.”

Moreover, “having a larger number of drugs with a range of mechanisms of action is extraordinarily helpful given how difficult the disease can be to manage. We will hopefully continue to see creative approaches and further successes in the current wave of phase 1, 2, and 3 trials that are already underway.”

The SUNSHINE and SUNRISE studies were funded by Novartis Pharma AG, Basel, Switzerland. The phase 2A study Dr. Kimball presented was sponsored by Pfizer.

Dr. Kimball disclosed ties to both Novartis and Pfizer and acts as a consultant and investigator to AbbVie, Bristol-Myers Squibb, Janssen, Eli Lilly, Novartis, and UCB. She is an investigator for Incyte and AnaptysBio; acts as a consultant to Bayer, Boehringer Ingelheim, Ventyz, Moonlake, Lily, Concert, EvoImmune, Sonoma Bio, and Sanofi; receives fellowship funding from Janssen, and serves on the Board of Directors for Almirall.

Dr. Patel had no conflicts of interest to disclose. Dr. Sayed is the director of the HS Foundation, a nonprofit organization, and has acted as an adviser or consultant to, speaker for, and received research funding from multiple drug companies including AbbVie, ChemoCentryx, Incyte, InflaRx, Novartis, and UCB.

A version of this article first appeared on Medscape.com.

Key clinical point: Lapatinib demonstrated excellent survival outcomes in patients with small, node-negative, human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC), when used in combination with trastuzumab, but not when used as a substitute for trastuzumab.

Major finding: The 7-year disease-free survival (DFS) rate in the overall cohort was excellent (88.1%), with improved DFS outcomes observed in the trastuzumab (89.6%), trastuzumab followed by lapatinib (89.0%), and trastuzumab+lapatinib (89.1%) arms, but not as much in the lapatinib-only arm (84.3%; stratified log-rank P   =   .031).

Study details: Findings are from a subanalysis of the phase 3 ALTTO trial including 2821 patients with small (pathological tumor size ≤ 3 cm), lymph node-negative, early HER2+ BC who were randomly assigned to receive adjuvant therapy with trastuzumab, lapatinib, trastuzumab followed by lapatinib, or trastuzumab+lapatinib.

Disclosures: The ALTTO trial received funding from GlaxoSmithKline, Novartis Pharma AG, and other sources. Two authors declared being employees of and owning stocks in Novartis. The other authors reported ties with several sources, including Novartis.

Source: Nader-Marta G et al. Outcomes of patients with small and node-negative HER2-positive early breast cancer treated with adjuvant chemotherapy and anti-HER2 therapy-a sub-analysis of the ALTTO study. Br J Cancer. 2022 (Sep 1). Doi: 10.1038/s41416-022-01963-8

Key clinical point: Lapatinib demonstrated excellent survival outcomes in patients with small, node-negative, human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC), when used in combination with trastuzumab, but not when used as a substitute for trastuzumab.

Major finding: The 7-year disease-free survival (DFS) rate in the overall cohort was excellent (88.1%), with improved DFS outcomes observed in the trastuzumab (89.6%), trastuzumab followed by lapatinib (89.0%), and trastuzumab+lapatinib (89.1%) arms, but not as much in the lapatinib-only arm (84.3%; stratified log-rank P   =   .031).

Study details: Findings are from a subanalysis of the phase 3 ALTTO trial including 2821 patients with small (pathological tumor size ≤ 3 cm), lymph node-negative, early HER2+ BC who were randomly assigned to receive adjuvant therapy with trastuzumab, lapatinib, trastuzumab followed by lapatinib, or trastuzumab+lapatinib.

Disclosures: The ALTTO trial received funding from GlaxoSmithKline, Novartis Pharma AG, and other sources. Two authors declared being employees of and owning stocks in Novartis. The other authors reported ties with several sources, including Novartis.

Source: Nader-Marta G et al. Outcomes of patients with small and node-negative HER2-positive early breast cancer treated with adjuvant chemotherapy and anti-HER2 therapy-a sub-analysis of the ALTTO study. Br J Cancer. 2022 (Sep 1). Doi: 10.1038/s41416-022-01963-8

Key clinical point: Lapatinib demonstrated excellent survival outcomes in patients with small, node-negative, human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC), when used in combination with trastuzumab, but not when used as a substitute for trastuzumab.

Major finding: The 7-year disease-free survival (DFS) rate in the overall cohort was excellent (88.1%), with improved DFS outcomes observed in the trastuzumab (89.6%), trastuzumab followed by lapatinib (89.0%), and trastuzumab+lapatinib (89.1%) arms, but not as much in the lapatinib-only arm (84.3%; stratified log-rank P   =   .031).

Study details: Findings are from a subanalysis of the phase 3 ALTTO trial including 2821 patients with small (pathological tumor size ≤ 3 cm), lymph node-negative, early HER2+ BC who were randomly assigned to receive adjuvant therapy with trastuzumab, lapatinib, trastuzumab followed by lapatinib, or trastuzumab+lapatinib.

Disclosures: The ALTTO trial received funding from GlaxoSmithKline, Novartis Pharma AG, and other sources. Two authors declared being employees of and owning stocks in Novartis. The other authors reported ties with several sources, including Novartis.

Source: Nader-Marta G et al. Outcomes of patients with small and node-negative HER2-positive early breast cancer treated with adjuvant chemotherapy and anti-HER2 therapy-a sub-analysis of the ALTTO study. Br J Cancer. 2022 (Sep 1). Doi: 10.1038/s41416-022-01963-8

Key clinical point: Neratinib as monotherapy or in combination with capecitabine showed good survival outcomes and was well tolerated in a real-world setting of patients with advanced human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) with or without brain metastases (BM).

Major finding: The median progression-free survival (PFS) and overall survival (OS) for all patients were 5.9 months (95% CI 4.9-7.4) and 15.0 months (95% CI 10.4-22.2), respectively, with survival outcomes being similar in patients with vs without BM. PFS and OS were significantly longer with neratinib+capecitabine vs neratinib (P ≤ .001). Diarrhea was the major adverse event (64%) with 10% being grade 3.

Study details: Findings are from a single-center retrospective study including 72 patients with advanced HER2+ BC who received neratinib (n = 27) or neratinib+capecitabine (n = 45). Thirty-eight patients had BM.

Disclosures: This study was supported by the Royal Marsden National Institute for Health and Care Research Biomedical Research Centre for Cancer, UK. The authors declared receiving research funding, speaker’s fees, honoraria, or travel support from several sources.

Source: Cunningham N et al. Neratinib in advanced HER2-positive breast cancer: Experience from the Royal Marsden Hospital. Breast Cancer Res Treat. 2022;195(3):333-340 (Aug 17). Doi: 10.1007/s10549-022-06703-3

Key clinical point: Neratinib as monotherapy or in combination with capecitabine showed good survival outcomes and was well tolerated in a real-world setting of patients with advanced human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) with or without brain metastases (BM).

Major finding: The median progression-free survival (PFS) and overall survival (OS) for all patients were 5.9 months (95% CI 4.9-7.4) and 15.0 months (95% CI 10.4-22.2), respectively, with survival outcomes being similar in patients with vs without BM. PFS and OS were significantly longer with neratinib+capecitabine vs neratinib (P ≤ .001). Diarrhea was the major adverse event (64%) with 10% being grade 3.

Study details: Findings are from a single-center retrospective study including 72 patients with advanced HER2+ BC who received neratinib (n = 27) or neratinib+capecitabine (n = 45). Thirty-eight patients had BM.

Disclosures: This study was supported by the Royal Marsden National Institute for Health and Care Research Biomedical Research Centre for Cancer, UK. The authors declared receiving research funding, speaker’s fees, honoraria, or travel support from several sources.

Source: Cunningham N et al. Neratinib in advanced HER2-positive breast cancer: Experience from the Royal Marsden Hospital. Breast Cancer Res Treat. 2022;195(3):333-340 (Aug 17). Doi: 10.1007/s10549-022-06703-3

Key clinical point: Neratinib as monotherapy or in combination with capecitabine showed good survival outcomes and was well tolerated in a real-world setting of patients with advanced human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) with or without brain metastases (BM).

Major finding: The median progression-free survival (PFS) and overall survival (OS) for all patients were 5.9 months (95% CI 4.9-7.4) and 15.0 months (95% CI 10.4-22.2), respectively, with survival outcomes being similar in patients with vs without BM. PFS and OS were significantly longer with neratinib+capecitabine vs neratinib (P ≤ .001). Diarrhea was the major adverse event (64%) with 10% being grade 3.

Study details: Findings are from a single-center retrospective study including 72 patients with advanced HER2+ BC who received neratinib (n = 27) or neratinib+capecitabine (n = 45). Thirty-eight patients had BM.

Disclosures: This study was supported by the Royal Marsden National Institute for Health and Care Research Biomedical Research Centre for Cancer, UK. The authors declared receiving research funding, speaker’s fees, honoraria, or travel support from several sources.

Source: Cunningham N et al. Neratinib in advanced HER2-positive breast cancer: Experience from the Royal Marsden Hospital. Breast Cancer Res Treat. 2022;195(3):333-340 (Aug 17). Doi: 10.1007/s10549-022-06703-3

Key clinical point: Addition of durvalumab to neoadjuvant chemotherapy (NACT) improved survival in women with early triple-negative breast cancer (TNBC) although improvement in the pathological complete response (pCR) rate was nonsignificant.

Major finding: In the overall cohort, durvalumab vs placebo improved 3-year invasive disease-free survival (hazard ratio [HR] 0.48; log-rank P   =   .036), distant disease-free survival (HR 0.31; log-rank P   =   .005), and overall survival (HR 0.24; log-rank P   =   .006) rates, despite no adjuvant component of durvalumab.

Study details: Findings are from the phase 2 GeparNuevo study including 174 patients with primary nonmetastatic TNBC who were randomly assigned to receive NACT with durvalumab or placebo.

Disclosures: This study was funded by AstraZeneca and Celgene. The authors declared receiving grants, personal fees, nonfinancial support, or other support from several sources.

Source: Loibl S et al. Neoadjuvant durvalumab improves survival in early triple-negative breast cancer independent of pathological complete response. Ann Oncol. 2022 (Aug 9). Doi: 10.1016/j.annonc.2022.07.1940

Key clinical point: Addition of durvalumab to neoadjuvant chemotherapy (NACT) improved survival in women with early triple-negative breast cancer (TNBC) although improvement in the pathological complete response (pCR) rate was nonsignificant.

Major finding: In the overall cohort, durvalumab vs placebo improved 3-year invasive disease-free survival (hazard ratio [HR] 0.48; log-rank P   =   .036), distant disease-free survival (HR 0.31; log-rank P   =   .005), and overall survival (HR 0.24; log-rank P   =   .006) rates, despite no adjuvant component of durvalumab.

Study details: Findings are from the phase 2 GeparNuevo study including 174 patients with primary nonmetastatic TNBC who were randomly assigned to receive NACT with durvalumab or placebo.

Disclosures: This study was funded by AstraZeneca and Celgene. The authors declared receiving grants, personal fees, nonfinancial support, or other support from several sources.

Source: Loibl S et al. Neoadjuvant durvalumab improves survival in early triple-negative breast cancer independent of pathological complete response. Ann Oncol. 2022 (Aug 9). Doi: 10.1016/j.annonc.2022.07.1940

Key clinical point: Addition of durvalumab to neoadjuvant chemotherapy (NACT) improved survival in women with early triple-negative breast cancer (TNBC) although improvement in the pathological complete response (pCR) rate was nonsignificant.

Major finding: In the overall cohort, durvalumab vs placebo improved 3-year invasive disease-free survival (hazard ratio [HR] 0.48; log-rank P   =   .036), distant disease-free survival (HR 0.31; log-rank P   =   .005), and overall survival (HR 0.24; log-rank P   =   .006) rates, despite no adjuvant component of durvalumab.

Study details: Findings are from the phase 2 GeparNuevo study including 174 patients with primary nonmetastatic TNBC who were randomly assigned to receive NACT with durvalumab or placebo.

Disclosures: This study was funded by AstraZeneca and Celgene. The authors declared receiving grants, personal fees, nonfinancial support, or other support from several sources.

Source: Loibl S et al. Neoadjuvant durvalumab improves survival in early triple-negative breast cancer independent of pathological complete response. Ann Oncol. 2022 (Aug 9). Doi: 10.1016/j.annonc.2022.07.1940

Key clinical point: Sacituzumab govitecan (SG) was more effective than chemotherapy in improving progression-free survival (PFS) and showed a manageable safety profile in patients with heavily pretreated, endocrine-resistant, hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (BC).

Major finding: SG vs chemotherapy significantly improved PFS (hazard ratio [HR] 0.66; P   =   .0003), with PFS rates being 46% vs 30% at 6 months and 21% vs 7% at 12 months, respectively. The most common grade ≥3 treatment-related adverse events with SG vs chemotherapy were neutropenia (51% vs 38%) and diarrhea (9% vs 1%).

Study details: Findings are the primary results of the phase 3 TROPiCS-02 trial including 543 patients with HR+/HER2− locally recurrent inoperable/metastatic BC who had received prior cyclin-dependent kinase 4/6 inhibitor with 2-4 lines of chemotherapy and were randomly assigned to receive SG or chemotherapy.

Disclosures: This study was supported by Gilead Sciences Inc. Four authors declared being employees of or stockowners in Gilead Sciences. The other authors reported ties with several sources, including Gilead.

Source: Rugo HS et al. Sacituzumab govitecan in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2022 (Aug 26). Doi: 10.1200/JCO.22.01002

Key clinical point: Sacituzumab govitecan (SG) was more effective than chemotherapy in improving progression-free survival (PFS) and showed a manageable safety profile in patients with heavily pretreated, endocrine-resistant, hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (BC).

Major finding: SG vs chemotherapy significantly improved PFS (hazard ratio [HR] 0.66; P   =   .0003), with PFS rates being 46% vs 30% at 6 months and 21% vs 7% at 12 months, respectively. The most common grade ≥3 treatment-related adverse events with SG vs chemotherapy were neutropenia (51% vs 38%) and diarrhea (9% vs 1%).

Study details: Findings are the primary results of the phase 3 TROPiCS-02 trial including 543 patients with HR+/HER2− locally recurrent inoperable/metastatic BC who had received prior cyclin-dependent kinase 4/6 inhibitor with 2-4 lines of chemotherapy and were randomly assigned to receive SG or chemotherapy.

Disclosures: This study was supported by Gilead Sciences Inc. Four authors declared being employees of or stockowners in Gilead Sciences. The other authors reported ties with several sources, including Gilead.

Source: Rugo HS et al. Sacituzumab govitecan in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2022 (Aug 26). Doi: 10.1200/JCO.22.01002

Key clinical point: Sacituzumab govitecan (SG) was more effective than chemotherapy in improving progression-free survival (PFS) and showed a manageable safety profile in patients with heavily pretreated, endocrine-resistant, hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (BC).

Major finding: SG vs chemotherapy significantly improved PFS (hazard ratio [HR] 0.66; P   =   .0003), with PFS rates being 46% vs 30% at 6 months and 21% vs 7% at 12 months, respectively. The most common grade ≥3 treatment-related adverse events with SG vs chemotherapy were neutropenia (51% vs 38%) and diarrhea (9% vs 1%).

Study details: Findings are the primary results of the phase 3 TROPiCS-02 trial including 543 patients with HR+/HER2− locally recurrent inoperable/metastatic BC who had received prior cyclin-dependent kinase 4/6 inhibitor with 2-4 lines of chemotherapy and were randomly assigned to receive SG or chemotherapy.

Disclosures: This study was supported by Gilead Sciences Inc. Four authors declared being employees of or stockowners in Gilead Sciences. The other authors reported ties with several sources, including Gilead.

Source: Rugo HS et al. Sacituzumab govitecan in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2022 (Aug 26). Doi: 10.1200/JCO.22.01002

Key clinical point: De-escalation of locoregional radiotherapy, according to a predefined consensus-based study guideline, was oncologically safe in women with cT1-2N1 breast cancer (BC) who received primary chemotherapy.

Major finding: The 5-year locoregional recurrence rate was 2.2% (95% CI 1.4%-3.4%) in the overall cohort, with the rates being similar in the low- vs intermediate-risk group (P   =   .89), low- vs high-risk group (P   =   .75), and intermediate- vs high-risk group (P   =   .83) and the 5-year locoregional recurrence rate remaining < 4% as per the study guideline.

Study details: Findings are from a prospective registry study including 838 patients with cT1-2N1 invasive BC who were treated with ≥3 cycles of primary chemotherapy and surgery of the breast and axillary and were categorized into three predefined risk categorized based on axillary lymph node status.

Disclosures: This study was funded by the Dutch Cancer Society. Some authors declared holding patents, serving as the chair of a committee, or receiving grants, consulting fees, or financial and nonfinancial support from several sources.

Source: de Wild SR et al. De-escalation of radiotherapy after primary chemotherapy in cT1-2N1 breast cancer (RAPCHEM; BOOG 2010-03): 5-year follow-up results of a Dutch, prospective, registry study. Lancet Oncol. 2022;23(9):1201-1210 (Aug 8). Doi: 10.1016/S1470-2045(22)00482-X

Key clinical point: De-escalation of locoregional radiotherapy, according to a predefined consensus-based study guideline, was oncologically safe in women with cT1-2N1 breast cancer (BC) who received primary chemotherapy.

Major finding: The 5-year locoregional recurrence rate was 2.2% (95% CI 1.4%-3.4%) in the overall cohort, with the rates being similar in the low- vs intermediate-risk group (P   =   .89), low- vs high-risk group (P   =   .75), and intermediate- vs high-risk group (P   =   .83) and the 5-year locoregional recurrence rate remaining < 4% as per the study guideline.

Study details: Findings are from a prospective registry study including 838 patients with cT1-2N1 invasive BC who were treated with ≥3 cycles of primary chemotherapy and surgery of the breast and axillary and were categorized into three predefined risk categorized based on axillary lymph node status.

Disclosures: This study was funded by the Dutch Cancer Society. Some authors declared holding patents, serving as the chair of a committee, or receiving grants, consulting fees, or financial and nonfinancial support from several sources.

Source: de Wild SR et al. De-escalation of radiotherapy after primary chemotherapy in cT1-2N1 breast cancer (RAPCHEM; BOOG 2010-03): 5-year follow-up results of a Dutch, prospective, registry study. Lancet Oncol. 2022;23(9):1201-1210 (Aug 8). Doi: 10.1016/S1470-2045(22)00482-X

Key clinical point: De-escalation of locoregional radiotherapy, according to a predefined consensus-based study guideline, was oncologically safe in women with cT1-2N1 breast cancer (BC) who received primary chemotherapy.

Major finding: The 5-year locoregional recurrence rate was 2.2% (95% CI 1.4%-3.4%) in the overall cohort, with the rates being similar in the low- vs intermediate-risk group (P   =   .89), low- vs high-risk group (P   =   .75), and intermediate- vs high-risk group (P   =   .83) and the 5-year locoregional recurrence rate remaining < 4% as per the study guideline.

Study details: Findings are from a prospective registry study including 838 patients with cT1-2N1 invasive BC who were treated with ≥3 cycles of primary chemotherapy and surgery of the breast and axillary and were categorized into three predefined risk categorized based on axillary lymph node status.

Disclosures: This study was funded by the Dutch Cancer Society. Some authors declared holding patents, serving as the chair of a committee, or receiving grants, consulting fees, or financial and nonfinancial support from several sources.

Source: de Wild SR et al. De-escalation of radiotherapy after primary chemotherapy in cT1-2N1 breast cancer (RAPCHEM; BOOG 2010-03): 5-year follow-up results of a Dutch, prospective, registry study. Lancet Oncol. 2022;23(9):1201-1210 (Aug 8). Doi: 10.1016/S1470-2045(22)00482-X

As reproductive specialists, part of our obligation is to improve a woman’s or couple’s ability to conceive in the most cost-effective manner, ideally through natural attempts at conception. While assisted reproductive technologies (ART) have provided impressive pregnancy rates across many diagnoses, including unexplained infertility, this advanced procedure comes with a significant financial cost to those without insurance and an emotional burden from the lack of a guaranteed outcome. Infertility procedures have minimal associated but potentially significant risks, most importantly multiple gestations. Contrary to popular belief, ovulation induction with intrauterine insemination (IUI) treatment has a greater risk of high-order multiple gestation when compared with IVF, given the inability of the former to control the number of embryos that may enter and implant in the endometrial cavity and the increased use of single embryo transfers with the latter. The specialist should evaluate the woman or couple for the basic issues of ovulation, tubal, and sperm function, as well as for lifestyle and environmental factors that can impede reproduction. As a result, “one size fits all” should not apply to patients, specifically those with infertility. This month’s column will present the detrimental effect of environmental and lifestyle factors on the goal of enhancing fertility through natural cycles of urine luteinizing-hormone timed intercourse.

Nutrition

Often overlooked in the infertility evaluation, an optimal diet improves fertility for both partners. Processed meat has been associated with reduced sperm quality. In ART, red meat has been associated with decreased embryo blastocyst formation. Lower trans fatty acids and higher omega-3s may improve fecundity. Considered one of the best overall diets, the Mediterranean diet consists of plant-based foods, such as whole grains, vegetables, legumes, fruits, nuts, seeds, herbs, and spices. Olive oil is the main source of added fat whereas fish, seafood, dairy, and poultry should be eaten in moderation. Fatty fish, such as mackerel, herring, sardines, albacore tuna, and salmon, are rich in omega-3 fatty acids, which have been shown to improve fecundity and IVF success, and have a positive association with blastocyst embryo development.^1-3

Stress

The emotional effect of an infertility diagnosis has been demonstrated to be equivalent to a diagnosis of cancer and other major medical morbidities.⁴ Whether stress causes or is a result of infertility has been a longstanding debate.⁵ Nevertheless, stress is the number-one reason patients discontinue fertility treatment.⁶ As fertility specialists, we must be cognizant of the devastation endured by infertility patients and maintain an open dialogue, as well as provide resources for coping strategies and counseling.

One popular method of improving mental health and fertility has been acupuncture. Initial enthusiasm originated from one of the first studies to explore the use of acupuncture during IVF. This was a prospective randomized study that showed treated patients had an approximately 100% improvement in clinical pregnancy rate. Unfortunately, there was no appropriate control group, just untreated controls.⁷ A subsequent study by the same investigator added a placebo acupuncture control group and did not show a statistically significant increase in pregnancy rates.⁸ Finally, a meta-analysis and reanalysis did not demonstrate any improvement in pregnancy outcome, whereas three of the studies analyzed suggested a possible reduction in pregnancies; placebo acupuncture was shown to have a higher success rate.^9-11 While acupuncture is relatively safe, there appears to be only a placebo effect that may be helpful.

The effect of stress on reproduction has been addressed in one of my previous columns.
 

Alcohol and caffeine

The damaging effects of alcohol on the fetus during pregnancy are legion – abnormal facial features, microcephaly, low birth weight, hyperactive behavior, vision or hearing deficits, speech and language delays, and intellectual disability. Less known is the amount of alcohol that may have an effect during preconception. One of the first reports on the effect of alcohol on IVF concluded: a 13% decrease in the number of eggs aspirated; a 2.86 times increase in risk of not achieving pregnancy; and a 2.21 times increase in risk of miscarriage. For men, one additional drink per day increased the risk of not achieving a live birth from 2.28 to 8.32 times.¹² Subsequent studies demonstrate a 16% reduction in IVF pregnancies in women who have at least four drinks per week; when the couple drank at least four drinks per week, the pregnancy rate decreased by 21%.¹³

However, a study from Denmark did not demonstrate a negative effect of low to moderate pretreatment amounts of alcohol and caffeine on IVF outcomes.¹⁴ Nevertheless, there is evidence that reducing or abstaining from alcohol intake may improve IVF outcomes.¹⁵ While there have been reports of higher miscarriage rates from caffeine,^16,17 not all reports support a negative association.¹⁸

Smoking

The use of tobacco has been estimated to contribute to 13% of female infertility in a dose-response manner, including secondhand smoke. During ART, smoking reduces ovarian response to gonadotropins and decreases IVF success by up to 50%. Discontinuing smoking for 6 months beforehand appears to restore normal outcomes.^19-20

The American Society for Reproductive Medicine Practice Committee on smoking provides the following invaluable information to share with patients on the harmful reproductive effects of smoking:²¹

• Early menopause by accelerating the loss of eggs.
• Higher rates of miscarriage and ectopic pregnancy.
• A decrease in sperm function.
• Possible genetic damage to eggs and sperm.
• Reduced sperm in son from maternal smoking.

Weight and exercise

Compared with normal-weight women, those with obesity are three times more likely to have ovulatory dysfunction;²² a lower chance for conception;²³ and infertility.²⁴ Obese women have higher rates of miscarriage and recurrent miscarriage, reduced success with ART, an increased number of canceled cycles, and poorer quality oocytes retrieved. During pregnancy, obese women have three to four times higher rates of gestational diabetes and preeclampsia,²⁵ as well as likelihood of having a fetus with macrosomia and birth defects, and a 1.3-2.1 times higher risk of stillbirth.²⁶

Regarding physical activity, the rate of pregnancies (39.0% vs. 16.0%, P = .002) and live births (24.4% vs. 7.4% (P = .004) were higher with regular exercise vs. being sedentary. Obese women who exercised regularly had a live birth rate over threefold higher compared with those who were not active.²⁷ Moderation should be employed given that women who exercise to exhaustion have 2.3 times the odds of fertility problems.²⁸ In men, obesity has been shown to increase estrogens and reduce spermatogenesis. Exercise has improved semen parameters and testosterone. Paternal physical and sedentary activities were not related to clinical pregnancy or live birth rates following infertility treatment.²⁹ As in women, men experience negative effects from high-intensity exercise, including bicycling, which can result in decreased semen parameters, follicle-stimulating hormone, LH, and testosterone levels.³⁰

In couples desiring a more natural approach to infertility, fertility specialists can address environmental and lifestyle factors that may improve reproduction. When natural attempts at conception are not applicable or successful, IUI and ART are appropriate treatment options after considering estimated success rates as well as the physical, emotional, and financial investment of patients.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
 

References

1. Wise LA et al. Am J Epidemiol. 2018;187:60-74.

2. Chui Y-H. Hum Reprod. 2018;33:156-65.

3. Ferreira Braga DPA et al. Reprod Biomed Online. 2015;31:30-8.

4. Domar AD et al. J Psychosom Obstet Gynaecol. 1993;14[suppl]:45-52.

5. Trolice MP. J Assist Reprod Genet. 2021 Apr;38[4]:873-5.

6. Gameiro S et al. Hum Reprod Update. 2012;18[6]:652-69.

7. Paulus WE et al. Fertil Steril. 2002;77:721-4.

8. Paulus WE et al. Hum Reprod. 2003;18:S18(abstr).

9. Wing SSE et al. Hum Reprod. 2009;24:341-8.

10. Hong Zheng C et al. Fertil Steril. 2012;97:599-611.

11. Meldrum DR et al. Fertil Steril. 2013;99:1821-4.

12. Klonoff-Cohen H et al. Fertil Steril. 2003;79:330-9.

13. Rossi BV et al. Obstet Gynecol. 2011;117:136-42.

14. Abadia L et al. Hum Reprod. 2017;32:1846-54.

15. Gormack AA et al. Hum Reprod. 2015;30:1617.

16. James JE. BMJ Evid Based Med. 2021;26:114-15.

17. Gaskins AJ et al. Eur J Nutr. 2018 Feb;57:107-17.

18. Machtinger R et al. Fertil Steril. 2017;108:1026-33.

19. Hughes EG et al. Fertil Steril. 1994;62:807.

20. de Ziegler D et al. Fertil Steril. 2013;100:927-8.

21. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2018;110:611-8.

22. Brewer CJ, Balen AH. Reproduction. 2010;140:347-64.

23. Wise LA et al. Hum Reprod. 2010;25:253-64.

24. Silvestris S et al. Reprod Biol Endocrinol. 2018;16[1]:22.

25. Alwash SM et al. Obes Res Clin Pract. 2021;15:425-30.

26. Aune D et al. JAMA. 2014;311:1536-46.

27. Palomba S et al. Reprod Biomed Online. 2014;29:72-9.

28. Gudmundsdottir SL et al. Hum Reprod. 2009;24[12]:3196-204.

29. Gaskins AJ et al. Hum Reprod. 2014;29:2575-82.

30. Wise LA et al. Fertil Steril. 2011;95:1025-30.

As reproductive specialists, part of our obligation is to improve a woman’s or couple’s ability to conceive in the most cost-effective manner, ideally through natural attempts at conception. While assisted reproductive technologies (ART) have provided impressive pregnancy rates across many diagnoses, including unexplained infertility, this advanced procedure comes with a significant financial cost to those without insurance and an emotional burden from the lack of a guaranteed outcome. Infertility procedures have minimal associated but potentially significant risks, most importantly multiple gestations. Contrary to popular belief, ovulation induction with intrauterine insemination (IUI) treatment has a greater risk of high-order multiple gestation when compared with IVF, given the inability of the former to control the number of embryos that may enter and implant in the endometrial cavity and the increased use of single embryo transfers with the latter. The specialist should evaluate the woman or couple for the basic issues of ovulation, tubal, and sperm function, as well as for lifestyle and environmental factors that can impede reproduction. As a result, “one size fits all” should not apply to patients, specifically those with infertility. This month’s column will present the detrimental effect of environmental and lifestyle factors on the goal of enhancing fertility through natural cycles of urine luteinizing-hormone timed intercourse.

Nutrition

Often overlooked in the infertility evaluation, an optimal diet improves fertility for both partners. Processed meat has been associated with reduced sperm quality. In ART, red meat has been associated with decreased embryo blastocyst formation. Lower trans fatty acids and higher omega-3s may improve fecundity. Considered one of the best overall diets, the Mediterranean diet consists of plant-based foods, such as whole grains, vegetables, legumes, fruits, nuts, seeds, herbs, and spices. Olive oil is the main source of added fat whereas fish, seafood, dairy, and poultry should be eaten in moderation. Fatty fish, such as mackerel, herring, sardines, albacore tuna, and salmon, are rich in omega-3 fatty acids, which have been shown to improve fecundity and IVF success, and have a positive association with blastocyst embryo development.^1-3

Stress

The emotional effect of an infertility diagnosis has been demonstrated to be equivalent to a diagnosis of cancer and other major medical morbidities.⁴ Whether stress causes or is a result of infertility has been a longstanding debate.⁵ Nevertheless, stress is the number-one reason patients discontinue fertility treatment.⁶ As fertility specialists, we must be cognizant of the devastation endured by infertility patients and maintain an open dialogue, as well as provide resources for coping strategies and counseling.

One popular method of improving mental health and fertility has been acupuncture. Initial enthusiasm originated from one of the first studies to explore the use of acupuncture during IVF. This was a prospective randomized study that showed treated patients had an approximately 100% improvement in clinical pregnancy rate. Unfortunately, there was no appropriate control group, just untreated controls.⁷ A subsequent study by the same investigator added a placebo acupuncture control group and did not show a statistically significant increase in pregnancy rates.⁸ Finally, a meta-analysis and reanalysis did not demonstrate any improvement in pregnancy outcome, whereas three of the studies analyzed suggested a possible reduction in pregnancies; placebo acupuncture was shown to have a higher success rate.^9-11 While acupuncture is relatively safe, there appears to be only a placebo effect that may be helpful.

The effect of stress on reproduction has been addressed in one of my previous columns.
 

Alcohol and caffeine

The damaging effects of alcohol on the fetus during pregnancy are legion – abnormal facial features, microcephaly, low birth weight, hyperactive behavior, vision or hearing deficits, speech and language delays, and intellectual disability. Less known is the amount of alcohol that may have an effect during preconception. One of the first reports on the effect of alcohol on IVF concluded: a 13% decrease in the number of eggs aspirated; a 2.86 times increase in risk of not achieving pregnancy; and a 2.21 times increase in risk of miscarriage. For men, one additional drink per day increased the risk of not achieving a live birth from 2.28 to 8.32 times.¹² Subsequent studies demonstrate a 16% reduction in IVF pregnancies in women who have at least four drinks per week; when the couple drank at least four drinks per week, the pregnancy rate decreased by 21%.¹³

However, a study from Denmark did not demonstrate a negative effect of low to moderate pretreatment amounts of alcohol and caffeine on IVF outcomes.¹⁴ Nevertheless, there is evidence that reducing or abstaining from alcohol intake may improve IVF outcomes.¹⁵ While there have been reports of higher miscarriage rates from caffeine,^16,17 not all reports support a negative association.¹⁸

Smoking

The use of tobacco has been estimated to contribute to 13% of female infertility in a dose-response manner, including secondhand smoke. During ART, smoking reduces ovarian response to gonadotropins and decreases IVF success by up to 50%. Discontinuing smoking for 6 months beforehand appears to restore normal outcomes.^19-20

The American Society for Reproductive Medicine Practice Committee on smoking provides the following invaluable information to share with patients on the harmful reproductive effects of smoking:²¹

• Early menopause by accelerating the loss of eggs.
• Higher rates of miscarriage and ectopic pregnancy.
• A decrease in sperm function.
• Possible genetic damage to eggs and sperm.
• Reduced sperm in son from maternal smoking.

Weight and exercise

Compared with normal-weight women, those with obesity are three times more likely to have ovulatory dysfunction;²² a lower chance for conception;²³ and infertility.²⁴ Obese women have higher rates of miscarriage and recurrent miscarriage, reduced success with ART, an increased number of canceled cycles, and poorer quality oocytes retrieved. During pregnancy, obese women have three to four times higher rates of gestational diabetes and preeclampsia,²⁵ as well as likelihood of having a fetus with macrosomia and birth defects, and a 1.3-2.1 times higher risk of stillbirth.²⁶

Regarding physical activity, the rate of pregnancies (39.0% vs. 16.0%, P = .002) and live births (24.4% vs. 7.4% (P = .004) were higher with regular exercise vs. being sedentary. Obese women who exercised regularly had a live birth rate over threefold higher compared with those who were not active.²⁷ Moderation should be employed given that women who exercise to exhaustion have 2.3 times the odds of fertility problems.²⁸ In men, obesity has been shown to increase estrogens and reduce spermatogenesis. Exercise has improved semen parameters and testosterone. Paternal physical and sedentary activities were not related to clinical pregnancy or live birth rates following infertility treatment.²⁹ As in women, men experience negative effects from high-intensity exercise, including bicycling, which can result in decreased semen parameters, follicle-stimulating hormone, LH, and testosterone levels.³⁰

In couples desiring a more natural approach to infertility, fertility specialists can address environmental and lifestyle factors that may improve reproduction. When natural attempts at conception are not applicable or successful, IUI and ART are appropriate treatment options after considering estimated success rates as well as the physical, emotional, and financial investment of patients.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
 

References

1. Wise LA et al. Am J Epidemiol. 2018;187:60-74.

2. Chui Y-H. Hum Reprod. 2018;33:156-65.

3. Ferreira Braga DPA et al. Reprod Biomed Online. 2015;31:30-8.

4. Domar AD et al. J Psychosom Obstet Gynaecol. 1993;14[suppl]:45-52.

5. Trolice MP. J Assist Reprod Genet. 2021 Apr;38[4]:873-5.

6. Gameiro S et al. Hum Reprod Update. 2012;18[6]:652-69.

7. Paulus WE et al. Fertil Steril. 2002;77:721-4.

8. Paulus WE et al. Hum Reprod. 2003;18:S18(abstr).

9. Wing SSE et al. Hum Reprod. 2009;24:341-8.

10. Hong Zheng C et al. Fertil Steril. 2012;97:599-611.

11. Meldrum DR et al. Fertil Steril. 2013;99:1821-4.

12. Klonoff-Cohen H et al. Fertil Steril. 2003;79:330-9.

13. Rossi BV et al. Obstet Gynecol. 2011;117:136-42.

14. Abadia L et al. Hum Reprod. 2017;32:1846-54.

15. Gormack AA et al. Hum Reprod. 2015;30:1617.

16. James JE. BMJ Evid Based Med. 2021;26:114-15.

17. Gaskins AJ et al. Eur J Nutr. 2018 Feb;57:107-17.

18. Machtinger R et al. Fertil Steril. 2017;108:1026-33.

19. Hughes EG et al. Fertil Steril. 1994;62:807.

20. de Ziegler D et al. Fertil Steril. 2013;100:927-8.

21. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2018;110:611-8.

22. Brewer CJ, Balen AH. Reproduction. 2010;140:347-64.

23. Wise LA et al. Hum Reprod. 2010;25:253-64.

24. Silvestris S et al. Reprod Biol Endocrinol. 2018;16[1]:22.

25. Alwash SM et al. Obes Res Clin Pract. 2021;15:425-30.

26. Aune D et al. JAMA. 2014;311:1536-46.

27. Palomba S et al. Reprod Biomed Online. 2014;29:72-9.

28. Gudmundsdottir SL et al. Hum Reprod. 2009;24[12]:3196-204.

29. Gaskins AJ et al. Hum Reprod. 2014;29:2575-82.

30. Wise LA et al. Fertil Steril. 2011;95:1025-30.

As reproductive specialists, part of our obligation is to improve a woman’s or couple’s ability to conceive in the most cost-effective manner, ideally through natural attempts at conception. While assisted reproductive technologies (ART) have provided impressive pregnancy rates across many diagnoses, including unexplained infertility, this advanced procedure comes with a significant financial cost to those without insurance and an emotional burden from the lack of a guaranteed outcome. Infertility procedures have minimal associated but potentially significant risks, most importantly multiple gestations. Contrary to popular belief, ovulation induction with intrauterine insemination (IUI) treatment has a greater risk of high-order multiple gestation when compared with IVF, given the inability of the former to control the number of embryos that may enter and implant in the endometrial cavity and the increased use of single embryo transfers with the latter. The specialist should evaluate the woman or couple for the basic issues of ovulation, tubal, and sperm function, as well as for lifestyle and environmental factors that can impede reproduction. As a result, “one size fits all” should not apply to patients, specifically those with infertility. This month’s column will present the detrimental effect of environmental and lifestyle factors on the goal of enhancing fertility through natural cycles of urine luteinizing-hormone timed intercourse.

Nutrition

Often overlooked in the infertility evaluation, an optimal diet improves fertility for both partners. Processed meat has been associated with reduced sperm quality. In ART, red meat has been associated with decreased embryo blastocyst formation. Lower trans fatty acids and higher omega-3s may improve fecundity. Considered one of the best overall diets, the Mediterranean diet consists of plant-based foods, such as whole grains, vegetables, legumes, fruits, nuts, seeds, herbs, and spices. Olive oil is the main source of added fat whereas fish, seafood, dairy, and poultry should be eaten in moderation. Fatty fish, such as mackerel, herring, sardines, albacore tuna, and salmon, are rich in omega-3 fatty acids, which have been shown to improve fecundity and IVF success, and have a positive association with blastocyst embryo development.^1-3

Stress

The emotional effect of an infertility diagnosis has been demonstrated to be equivalent to a diagnosis of cancer and other major medical morbidities.⁴ Whether stress causes or is a result of infertility has been a longstanding debate.⁵ Nevertheless, stress is the number-one reason patients discontinue fertility treatment.⁶ As fertility specialists, we must be cognizant of the devastation endured by infertility patients and maintain an open dialogue, as well as provide resources for coping strategies and counseling.

One popular method of improving mental health and fertility has been acupuncture. Initial enthusiasm originated from one of the first studies to explore the use of acupuncture during IVF. This was a prospective randomized study that showed treated patients had an approximately 100% improvement in clinical pregnancy rate. Unfortunately, there was no appropriate control group, just untreated controls.⁷ A subsequent study by the same investigator added a placebo acupuncture control group and did not show a statistically significant increase in pregnancy rates.⁸ Finally, a meta-analysis and reanalysis did not demonstrate any improvement in pregnancy outcome, whereas three of the studies analyzed suggested a possible reduction in pregnancies; placebo acupuncture was shown to have a higher success rate.^9-11 While acupuncture is relatively safe, there appears to be only a placebo effect that may be helpful.

The effect of stress on reproduction has been addressed in one of my previous columns.
 

Alcohol and caffeine

The damaging effects of alcohol on the fetus during pregnancy are legion – abnormal facial features, microcephaly, low birth weight, hyperactive behavior, vision or hearing deficits, speech and language delays, and intellectual disability. Less known is the amount of alcohol that may have an effect during preconception. One of the first reports on the effect of alcohol on IVF concluded: a 13% decrease in the number of eggs aspirated; a 2.86 times increase in risk of not achieving pregnancy; and a 2.21 times increase in risk of miscarriage. For men, one additional drink per day increased the risk of not achieving a live birth from 2.28 to 8.32 times.¹² Subsequent studies demonstrate a 16% reduction in IVF pregnancies in women who have at least four drinks per week; when the couple drank at least four drinks per week, the pregnancy rate decreased by 21%.¹³

However, a study from Denmark did not demonstrate a negative effect of low to moderate pretreatment amounts of alcohol and caffeine on IVF outcomes.¹⁴ Nevertheless, there is evidence that reducing or abstaining from alcohol intake may improve IVF outcomes.¹⁵ While there have been reports of higher miscarriage rates from caffeine,^16,17 not all reports support a negative association.¹⁸

Smoking

The use of tobacco has been estimated to contribute to 13% of female infertility in a dose-response manner, including secondhand smoke. During ART, smoking reduces ovarian response to gonadotropins and decreases IVF success by up to 50%. Discontinuing smoking for 6 months beforehand appears to restore normal outcomes.^19-20

The American Society for Reproductive Medicine Practice Committee on smoking provides the following invaluable information to share with patients on the harmful reproductive effects of smoking:²¹

• Early menopause by accelerating the loss of eggs.
• Higher rates of miscarriage and ectopic pregnancy.
• A decrease in sperm function.
• Possible genetic damage to eggs and sperm.
• Reduced sperm in son from maternal smoking.

Weight and exercise

Compared with normal-weight women, those with obesity are three times more likely to have ovulatory dysfunction;²² a lower chance for conception;²³ and infertility.²⁴ Obese women have higher rates of miscarriage and recurrent miscarriage, reduced success with ART, an increased number of canceled cycles, and poorer quality oocytes retrieved. During pregnancy, obese women have three to four times higher rates of gestational diabetes and preeclampsia,²⁵ as well as likelihood of having a fetus with macrosomia and birth defects, and a 1.3-2.1 times higher risk of stillbirth.²⁶

Regarding physical activity, the rate of pregnancies (39.0% vs. 16.0%, P = .002) and live births (24.4% vs. 7.4% (P = .004) were higher with regular exercise vs. being sedentary. Obese women who exercised regularly had a live birth rate over threefold higher compared with those who were not active.²⁷ Moderation should be employed given that women who exercise to exhaustion have 2.3 times the odds of fertility problems.²⁸ In men, obesity has been shown to increase estrogens and reduce spermatogenesis. Exercise has improved semen parameters and testosterone. Paternal physical and sedentary activities were not related to clinical pregnancy or live birth rates following infertility treatment.²⁹ As in women, men experience negative effects from high-intensity exercise, including bicycling, which can result in decreased semen parameters, follicle-stimulating hormone, LH, and testosterone levels.³⁰

In couples desiring a more natural approach to infertility, fertility specialists can address environmental and lifestyle factors that may improve reproduction. When natural attempts at conception are not applicable or successful, IUI and ART are appropriate treatment options after considering estimated success rates as well as the physical, emotional, and financial investment of patients.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
 

References

1. Wise LA et al. Am J Epidemiol. 2018;187:60-74.

2. Chui Y-H. Hum Reprod. 2018;33:156-65.

3. Ferreira Braga DPA et al. Reprod Biomed Online. 2015;31:30-8.

4. Domar AD et al. J Psychosom Obstet Gynaecol. 1993;14[suppl]:45-52.

5. Trolice MP. J Assist Reprod Genet. 2021 Apr;38[4]:873-5.

6. Gameiro S et al. Hum Reprod Update. 2012;18[6]:652-69.

7. Paulus WE et al. Fertil Steril. 2002;77:721-4.

8. Paulus WE et al. Hum Reprod. 2003;18:S18(abstr).

9. Wing SSE et al. Hum Reprod. 2009;24:341-8.

10. Hong Zheng C et al. Fertil Steril. 2012;97:599-611.

11. Meldrum DR et al. Fertil Steril. 2013;99:1821-4.

12. Klonoff-Cohen H et al. Fertil Steril. 2003;79:330-9.

13. Rossi BV et al. Obstet Gynecol. 2011;117:136-42.

14. Abadia L et al. Hum Reprod. 2017;32:1846-54.

15. Gormack AA et al. Hum Reprod. 2015;30:1617.

16. James JE. BMJ Evid Based Med. 2021;26:114-15.

17. Gaskins AJ et al. Eur J Nutr. 2018 Feb;57:107-17.

18. Machtinger R et al. Fertil Steril. 2017;108:1026-33.

19. Hughes EG et al. Fertil Steril. 1994;62:807.

20. de Ziegler D et al. Fertil Steril. 2013;100:927-8.

21. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2018;110:611-8.

22. Brewer CJ, Balen AH. Reproduction. 2010;140:347-64.

23. Wise LA et al. Hum Reprod. 2010;25:253-64.

24. Silvestris S et al. Reprod Biol Endocrinol. 2018;16[1]:22.

25. Alwash SM et al. Obes Res Clin Pract. 2021;15:425-30.

26. Aune D et al. JAMA. 2014;311:1536-46.

27. Palomba S et al. Reprod Biomed Online. 2014;29:72-9.

28. Gudmundsdottir SL et al. Hum Reprod. 2009;24[12]:3196-204.

29. Gaskins AJ et al. Hum Reprod. 2014;29:2575-82.

30. Wise LA et al. Fertil Steril. 2011;95:1025-30.