Kevin Kalinsky, MD, MS

Breast cancer (BC) is the most diagnosed cancer and the second leading cause of cancer deaths in women. In 2022, more than 275,000 women were diagnosed with BC, and at least 43,000 of these cases resulted in death. With targeted drug therapy for treating BC now approved by the US Food and Drug Administration (FDA) and available (or in the late phases of clinical trials and pending availability and FDA approval), clinicians are beginning to be able to move away from a “one-size-fits-all” treatment approach that has been used in the past, enhancing prognosis and survival rates in their patients living with BC. 

The new targeted drug therapies available are more precise and individualized. They treat patients more effectively because they are based on the patient’s own biology. These therapies open the possibility of having more valuable treatment options, which can be beneficial for the outcome of many patients diagnosed with BC—especially the highly aggressive forms that were previously difficult to treat. 

In March 2022, the FDA approved the drug olaparib to treat HER2-, high-risk, early breast cancer (EBC). The approval was made after the conclusion of the phase 3 OlympiA trial. The clinical trial results showed a statistically significant improvement in overall survival rates (by 32%) with adjuvant olaparib compared with placebo for germline BRCA1/2-mutated EBC. 

In August 2022, the FDA approved the antibody drug conjugate fam-trastuzumab deruxtecan-nxki (or T-DXd), which is the first FDA-approved therapy targeted to treat patients who have the HER2-low BC subtype. It is also approved for patients with unresectable or metastatic HER2+ breast cancer who have already been treated with 2 or more prior anti-HER2–based therapies in the metastatic setting. The approval of T-DXd was given on the basis of DESTINY-Breast04, a randomized, multicenter, open-label clinical trial that was published in June 2022. T-DXd had been previously approved in HER2+ metastatic breast cancer.

The results from the phase 3 CAPItello-291 clinical trial of capivasertib in combination with fulvestrant suggests the combination could become a new treatment option for patients with hormone receptor–positive, HER2-low, locally advanced or metastatic BC following recurrence or progression after treatment with endocrine therapy and a CDK4/6 inhibitor. Capivasertib is a novel, selective, ATP-competitive, pan-AKT kinase inhibitor. In clinical trials, the drug was shown to successfully block activity of the cancer-driving protein molecule AKT. This research was presented at the 2022 San Antonio Breast Cancer Symposium, and the findings demonstrated a significant improvement in the overall population, as well as the subgroup of patients with PI3K pathway–altered tumors.

The year 2022 was full of exciting discoveries in the field of targeted drug therapies for treating BC, expanding patients’ treatment options and giving hope to people who have been diagnosed with breast cancer and their loved ones. In addition, emerging technologies such as immunotherapy and new antibody-drug conjugates continue to be evaluated as potential treatment options for treating breast cancer in the near future.

Breast cancer (BC) is the most diagnosed cancer and the second leading cause of cancer deaths in women. In 2022, more than 275,000 women were diagnosed with BC, and at least 43,000 of these cases resulted in death. With targeted drug therapy for treating BC now approved by the US Food and Drug Administration (FDA) and available (or in the late phases of clinical trials and pending availability and FDA approval), clinicians are beginning to be able to move away from a “one-size-fits-all” treatment approach that has been used in the past, enhancing prognosis and survival rates in their patients living with BC. 

The new targeted drug therapies available are more precise and individualized. They treat patients more effectively because they are based on the patient’s own biology. These therapies open the possibility of having more valuable treatment options, which can be beneficial for the outcome of many patients diagnosed with BC—especially the highly aggressive forms that were previously difficult to treat. 

In March 2022, the FDA approved the drug olaparib to treat HER2-, high-risk, early breast cancer (EBC). The approval was made after the conclusion of the phase 3 OlympiA trial. The clinical trial results showed a statistically significant improvement in overall survival rates (by 32%) with adjuvant olaparib compared with placebo for germline BRCA1/2-mutated EBC. 

In August 2022, the FDA approved the antibody drug conjugate fam-trastuzumab deruxtecan-nxki (or T-DXd), which is the first FDA-approved therapy targeted to treat patients who have the HER2-low BC subtype. It is also approved for patients with unresectable or metastatic HER2+ breast cancer who have already been treated with 2 or more prior anti-HER2–based therapies in the metastatic setting. The approval of T-DXd was given on the basis of DESTINY-Breast04, a randomized, multicenter, open-label clinical trial that was published in June 2022. T-DXd had been previously approved in HER2+ metastatic breast cancer.

The results from the phase 3 CAPItello-291 clinical trial of capivasertib in combination with fulvestrant suggests the combination could become a new treatment option for patients with hormone receptor–positive, HER2-low, locally advanced or metastatic BC following recurrence or progression after treatment with endocrine therapy and a CDK4/6 inhibitor. Capivasertib is a novel, selective, ATP-competitive, pan-AKT kinase inhibitor. In clinical trials, the drug was shown to successfully block activity of the cancer-driving protein molecule AKT. This research was presented at the 2022 San Antonio Breast Cancer Symposium, and the findings demonstrated a significant improvement in the overall population, as well as the subgroup of patients with PI3K pathway–altered tumors.

The year 2022 was full of exciting discoveries in the field of targeted drug therapies for treating BC, expanding patients’ treatment options and giving hope to people who have been diagnosed with breast cancer and their loved ones. In addition, emerging technologies such as immunotherapy and new antibody-drug conjugates continue to be evaluated as potential treatment options for treating breast cancer in the near future.

Breast cancer (BC) is the most diagnosed cancer and the second leading cause of cancer deaths in women. In 2022, more than 275,000 women were diagnosed with BC, and at least 43,000 of these cases resulted in death. With targeted drug therapy for treating BC now approved by the US Food and Drug Administration (FDA) and available (or in the late phases of clinical trials and pending availability and FDA approval), clinicians are beginning to be able to move away from a “one-size-fits-all” treatment approach that has been used in the past, enhancing prognosis and survival rates in their patients living with BC. 

The new targeted drug therapies available are more precise and individualized. They treat patients more effectively because they are based on the patient’s own biology. These therapies open the possibility of having more valuable treatment options, which can be beneficial for the outcome of many patients diagnosed with BC—especially the highly aggressive forms that were previously difficult to treat. 

In March 2022, the FDA approved the drug olaparib to treat HER2-, high-risk, early breast cancer (EBC). The approval was made after the conclusion of the phase 3 OlympiA trial. The clinical trial results showed a statistically significant improvement in overall survival rates (by 32%) with adjuvant olaparib compared with placebo for germline BRCA1/2-mutated EBC. 

In August 2022, the FDA approved the antibody drug conjugate fam-trastuzumab deruxtecan-nxki (or T-DXd), which is the first FDA-approved therapy targeted to treat patients who have the HER2-low BC subtype. It is also approved for patients with unresectable or metastatic HER2+ breast cancer who have already been treated with 2 or more prior anti-HER2–based therapies in the metastatic setting. The approval of T-DXd was given on the basis of DESTINY-Breast04, a randomized, multicenter, open-label clinical trial that was published in June 2022. T-DXd had been previously approved in HER2+ metastatic breast cancer.

The results from the phase 3 CAPItello-291 clinical trial of capivasertib in combination with fulvestrant suggests the combination could become a new treatment option for patients with hormone receptor–positive, HER2-low, locally advanced or metastatic BC following recurrence or progression after treatment with endocrine therapy and a CDK4/6 inhibitor. Capivasertib is a novel, selective, ATP-competitive, pan-AKT kinase inhibitor. In clinical trials, the drug was shown to successfully block activity of the cancer-driving protein molecule AKT. This research was presented at the 2022 San Antonio Breast Cancer Symposium, and the findings demonstrated a significant improvement in the overall population, as well as the subgroup of patients with PI3K pathway–altered tumors.

The year 2022 was full of exciting discoveries in the field of targeted drug therapies for treating BC, expanding patients’ treatment options and giving hope to people who have been diagnosed with breast cancer and their loved ones. In addition, emerging technologies such as immunotherapy and new antibody-drug conjugates continue to be evaluated as potential treatment options for treating breast cancer in the near future.

As both a clinician and investigator in the breast cancer space, how would you describe our current understanding of genomic assays in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative disease?

Dr. Kalinsky: There are a number of commercially-available assays for patients with early-stage HR-positive/HER2-negative breast cancer. We have seen the results of 3 large randomized phase 3 trials that have demonstrated and helped establish the clinical utility of assays, including the oncotype DX 21-gene recurrence score. This was evaluated in patients with node-negative breast cancer in the TAILORx trial and in patients with 1 to 3 nodes involved in the RxPONDER trial.

We also have data with the 70-gene MammaPrint assay from the MINDACT study, looking for patients who had a discordance between clinical and genomic risk. MINDACT has been published and was updated recently with data for 8-year distant metastasis-free survival. It is these studies that have helped establish what we do in the clinic and when we consider offering genomic assays in patients with this subtype of breast cancer.

How are you working to bring these genomic assays into practice?

Dr. Kalinsky: In 2020, we reported the initial results from the RxPonder study demonstrating that for patients with HR-positive HER2-negative breast cancer with 1 to 3 nodes involved, two-thirds of the patients were postmenopausal. For patients who had a recurrence score of 25 or less, we did not identify a subgroup of patients who benefited from chemotherapy.

For the premenopausal women, which was one-third of the patients, we saw that all those patients benefited from the addition of chemotherapy if the recurrence score was 25 or less. We did a number of subgroup analyses, which we reported on at the San Antonio Breast Cancer Symposium in 2021.

Several analyses are ongoing. These include some subgroup analyses looking at quality of life as well as a collection of circulating markers. In addition, there is ongoing biomarker work looking at tumor tissue to see if there are differences between the biology of premenopausal versus postmenopausal women.

What value does genomic testing bring to the treatment of HR-positive/HER2-negative breast cancer?

Dr. Kalinsky: These assays have achieved clinical utility, and this has been reflected in the recent update to the ASCO Guidelines for genomic assays. We have also learned that it is not just the assay by itself, but also the clinical features of a patient that help determine risk. In other words, it’s not just dependent on the score, but also involves the context of other important clinical features, including patient and tumor characteristics such as tumor size, patient age, and tumor grade. All of these add value and help us assess a patient’s individualized risk.

Is there a specific profile or qualifications candidates must meet for genomic testing to be done?

Dr. Kalinsky: We offer genomic tests for patients with HR-positive/HER2-negative breast cancer who are node-negative or have 1 to 3 nodes involved. There are other commercially-available tests such as the Breast Cancer Index, which assesses risk of recurrence in years 5 to 10 and looks at whether there is potential utility for continuing anti-estrogen therapy. That assay provides both prognostic and predictive information.

Is there any additional insight on genomic assays in HR-positive/HER2-negative breast cancer you would like to share?

Dr. Kalinsky: We’ve been talking about tumor-based assays. However, the question is, what’s going to be the role for circulating markers, such as circulating tumor DNA (ctDNA) or circulating tumor cells? There is a lot of information that we’re hoping to understand, not just regarding the prognostic significance but also the predictive utility. If you have a patient with a subtype of breast cancer and we know this subgroup can be at risk for late recurrence, if you identify said marker and you switch the therapy, do you see clearance of ctDNA? Does that lead to an improvement in outcome? That is an important question that is going to be answered in current and future trials.

As both a clinician and investigator in the breast cancer space, how would you describe our current understanding of genomic assays in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative disease?

Dr. Kalinsky: There are a number of commercially-available assays for patients with early-stage HR-positive/HER2-negative breast cancer. We have seen the results of 3 large randomized phase 3 trials that have demonstrated and helped establish the clinical utility of assays, including the oncotype DX 21-gene recurrence score. This was evaluated in patients with node-negative breast cancer in the TAILORx trial and in patients with 1 to 3 nodes involved in the RxPONDER trial.

We also have data with the 70-gene MammaPrint assay from the MINDACT study, looking for patients who had a discordance between clinical and genomic risk. MINDACT has been published and was updated recently with data for 8-year distant metastasis-free survival. It is these studies that have helped establish what we do in the clinic and when we consider offering genomic assays in patients with this subtype of breast cancer.

How are you working to bring these genomic assays into practice?

Dr. Kalinsky: In 2020, we reported the initial results from the RxPonder study demonstrating that for patients with HR-positive HER2-negative breast cancer with 1 to 3 nodes involved, two-thirds of the patients were postmenopausal. For patients who had a recurrence score of 25 or less, we did not identify a subgroup of patients who benefited from chemotherapy.

For the premenopausal women, which was one-third of the patients, we saw that all those patients benefited from the addition of chemotherapy if the recurrence score was 25 or less. We did a number of subgroup analyses, which we reported on at the San Antonio Breast Cancer Symposium in 2021.

Several analyses are ongoing. These include some subgroup analyses looking at quality of life as well as a collection of circulating markers. In addition, there is ongoing biomarker work looking at tumor tissue to see if there are differences between the biology of premenopausal versus postmenopausal women.

What value does genomic testing bring to the treatment of HR-positive/HER2-negative breast cancer?

Dr. Kalinsky: These assays have achieved clinical utility, and this has been reflected in the recent update to the ASCO Guidelines for genomic assays. We have also learned that it is not just the assay by itself, but also the clinical features of a patient that help determine risk. In other words, it’s not just dependent on the score, but also involves the context of other important clinical features, including patient and tumor characteristics such as tumor size, patient age, and tumor grade. All of these add value and help us assess a patient’s individualized risk.

Is there a specific profile or qualifications candidates must meet for genomic testing to be done?

Dr. Kalinsky: We offer genomic tests for patients with HR-positive/HER2-negative breast cancer who are node-negative or have 1 to 3 nodes involved. There are other commercially-available tests such as the Breast Cancer Index, which assesses risk of recurrence in years 5 to 10 and looks at whether there is potential utility for continuing anti-estrogen therapy. That assay provides both prognostic and predictive information.

Is there any additional insight on genomic assays in HR-positive/HER2-negative breast cancer you would like to share?

Dr. Kalinsky: We’ve been talking about tumor-based assays. However, the question is, what’s going to be the role for circulating markers, such as circulating tumor DNA (ctDNA) or circulating tumor cells? There is a lot of information that we’re hoping to understand, not just regarding the prognostic significance but also the predictive utility. If you have a patient with a subtype of breast cancer and we know this subgroup can be at risk for late recurrence, if you identify said marker and you switch the therapy, do you see clearance of ctDNA? Does that lead to an improvement in outcome? That is an important question that is going to be answered in current and future trials.

As both a clinician and investigator in the breast cancer space, how would you describe our current understanding of genomic assays in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative disease?

Dr. Kalinsky: There are a number of commercially-available assays for patients with early-stage HR-positive/HER2-negative breast cancer. We have seen the results of 3 large randomized phase 3 trials that have demonstrated and helped establish the clinical utility of assays, including the oncotype DX 21-gene recurrence score. This was evaluated in patients with node-negative breast cancer in the TAILORx trial and in patients with 1 to 3 nodes involved in the RxPONDER trial.

We also have data with the 70-gene MammaPrint assay from the MINDACT study, looking for patients who had a discordance between clinical and genomic risk. MINDACT has been published and was updated recently with data for 8-year distant metastasis-free survival. It is these studies that have helped establish what we do in the clinic and when we consider offering genomic assays in patients with this subtype of breast cancer.

How are you working to bring these genomic assays into practice?

Dr. Kalinsky: In 2020, we reported the initial results from the RxPonder study demonstrating that for patients with HR-positive HER2-negative breast cancer with 1 to 3 nodes involved, two-thirds of the patients were postmenopausal. For patients who had a recurrence score of 25 or less, we did not identify a subgroup of patients who benefited from chemotherapy.

For the premenopausal women, which was one-third of the patients, we saw that all those patients benefited from the addition of chemotherapy if the recurrence score was 25 or less. We did a number of subgroup analyses, which we reported on at the San Antonio Breast Cancer Symposium in 2021.

Several analyses are ongoing. These include some subgroup analyses looking at quality of life as well as a collection of circulating markers. In addition, there is ongoing biomarker work looking at tumor tissue to see if there are differences between the biology of premenopausal versus postmenopausal women.

What value does genomic testing bring to the treatment of HR-positive/HER2-negative breast cancer?

Dr. Kalinsky: These assays have achieved clinical utility, and this has been reflected in the recent update to the ASCO Guidelines for genomic assays. We have also learned that it is not just the assay by itself, but also the clinical features of a patient that help determine risk. In other words, it’s not just dependent on the score, but also involves the context of other important clinical features, including patient and tumor characteristics such as tumor size, patient age, and tumor grade. All of these add value and help us assess a patient’s individualized risk.

Is there a specific profile or qualifications candidates must meet for genomic testing to be done?

Dr. Kalinsky: We offer genomic tests for patients with HR-positive/HER2-negative breast cancer who are node-negative or have 1 to 3 nodes involved. There are other commercially-available tests such as the Breast Cancer Index, which assesses risk of recurrence in years 5 to 10 and looks at whether there is potential utility for continuing anti-estrogen therapy. That assay provides both prognostic and predictive information.

Is there any additional insight on genomic assays in HR-positive/HER2-negative breast cancer you would like to share?

Dr. Kalinsky: We’ve been talking about tumor-based assays. However, the question is, what’s going to be the role for circulating markers, such as circulating tumor DNA (ctDNA) or circulating tumor cells? There is a lot of information that we’re hoping to understand, not just regarding the prognostic significance but also the predictive utility. If you have a patient with a subtype of breast cancer and we know this subgroup can be at risk for late recurrence, if you identify said marker and you switch the therapy, do you see clearance of ctDNA? Does that lead to an improvement in outcome? That is an important question that is going to be answered in current and future trials.