Tag: Breast Cancer

Late Breaking Abstract – ASCO 2024: ENHERTU® Improves PFS in HR-Positive, HER2-Low and HER-Ultralow Metastatic Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with high levels of HER2 expression (IHC 3+ or 2+/FISH+) are classified as HER2-positive. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. Tumors that are not classified as HER2-positive are classified as HER2-negative. Despite being classified as HER2-negative, majority these tumors still have some level of HER2 expression.

About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor (HR)-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. It is estimated that approximately 60-65% of HR-positive/HER2-negative breast cancers are HER2-low and potentially an additional 25% may be HER2-ultralow. These patients are often treated with single agent endocrine therapy, endocrine therapy in combination with CDK4/6 inhibitor, or chemotherapy. Resistance to hormonal therapy occurs in a majority of the patients and there is therefore an unmet need for agents with novel mechanisms of action. Further, there are no targeted therapies specifically approved for patients with HER2-low or HER2-ultralow expression, prior to chemotherapy.

ENHERTU® (Trastuzumab Deruxtecan) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). ENHERTU® has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike KADCYLA® (ado-Trastuzumab emtansine), another ADC targeting HER2, ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, thus minimizing systemic exposure.

DESTINY-Breast06 is a global, randomized, open-label Phase III trial evaluating the efficacy and safety of ENHERTU® versus chemotherapy in patients with HR-positive, HER2-low, or HER2-ultralow advanced or metastatic breast cancer. This study enrolled 866 patients (N=713 for HER2-low and N=153 for HER2-ultralow). HER2-low was defined as IHC 1+ or 2+ or FISH negative and HER2-ultralow was defined as IHC 0 with membrane staining. Patients were randomized 1:1 to receive ENHERTU® 5.4 mg/kg every 3 weeks (N=436) or physicians choice of chemotherapy which included Capecitabine, Paclitaxel, or nab-Paclitaxel (N=430). Patients in the trial had no prior chemotherapy for advanced or metastatic disease and received at least two lines of prior endocrine therapy in the metastatic setting. Patients were also eligible if they had received one prior line of endocrine therapy combined with a CDK4/6 inhibitor in the metastatic setting and experienced disease progression within six months of starting 1st-line treatment, or received endocrine therapy as an adjuvant treatment and experienced disease recurrence within 24 months. Patients were stratified based on prior CDK4/6 inhibitor use, HER2 expression and prior taxane use in the non-metastatic setting. Patients in the trial had received a median of two prior lines of endocrine therapy. In the overall trial population, 14.9% of patients in the ENHERTU® group and 19.2% in the chemotherapy group had received one prior line of endocrine therapy. No patients had received prior chemotherapy for metastatic disease. The Primary endpoint was Progression Free Survival (PFS) in the HER2-low patient population as measured by Blinded Independent Central Review (BICR). Key Secondary endpoints included Progression Free Survival (PFS) in the overall trial population (HER2-low and HER2-ultralow), Overall survival (OS) in the HER2-low patient population, Objective Response Rate (ORR), Duration of response (DOR) and Safety. The median duration of follow-up was 18.2 months.

In the primary analysis of this study, results showed that in the HER2-low expression patients, ENHERTU® reduced the risk of disease progression or death by 38%, with a median PFS was 13.2 months in the ENHERTU® group, compared to 8.1 months for chemotherapy (HR=0.62; P<0.0001). For the overall trial population (HER2-low and HER2-ultralow), the median PFS results were similar and the median PFS was 13.2 months for ENHERTU® versus 8.1 months for chemotherapy (HR=0.63; P<0.0001). ENHERTU® reduced the risk of disease progression or death by 37% compared to chemotherapy.

A prespecified exploratory analysis showed that the improvement in PFS was consistent between patients with HER2-low and HER2-ultralow expression. In patients with HER2-ultralow expression, ENHERTU® reduced the risk of disease progression or death by 22% compared to chemotherapy, with a median PFS of 13.2 months versus 8.3 months, respectively (HR=0.78).

The Objective Response Rate (ORR) in HER2-Low Population was 56.5% for ENHERTU® compared to 32.2% for chemotherapy, in the Overall Trial Population was 57.3% for ENHERTU® versus 31.2% for chemotherapy, and in the HER2-Ultralow Subgroup was 61.8% for ENHERTU® versus 26.3% for chemotherapy. The median duration of response across these three groups was 14.3 months.

The safety profile of ENHERTU® was consistent with previous breast cancer clinical trials and no new safety concerns identified. The most common Grade 3 or higher treatment-related adverse events occurring in 5% or more of patients treated with ENHERTU® were neutropenia (20.7%) and anemia (5.8%). Interstitial Lung Disease (ILD), adjudicated as drug-related by an independent committee, occurred in 11.3% of patients treated with ENHERTU®. The majority of ILD events were low grade.

The results from the DESTINY-Breast06 trial underscore the significant clinical benefits of ENHERTU® in improving PFS and ORR in patients with HR-positive, HER2-low, and HER2-ultralow metastatic breast cancer, offering a promising alternative to standard chemotherapy. These findings highlight the potential of ENHERTU® to become a new standard of care for this patient population, pending further investigation and regulatory approval. The detailed positive outcomes underscore the clinical benefits and reinforce the promise of ENHERTU® in treating this challenging cancer subtype.

Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): Primary results from DESTINY-Breast06 (DB-06). Curigliano G, Hu X, Dent RA, et al. J Clin Oncol. 2024;42(suppl 17):LBA1000. doi:10.1200/JCO.2024.42.17_suppl.LBA1000.

Benign Breast Disease and Increased Breast Cancer Risk

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 310,720 new cases of breast cancer were diagnosed in 2024 and about 42,250 individuals will die of the disease, largely due to metastatic recurrence. Breast cancer is the second leading cause of cancer death in women, in the U.S.

Benign breast disease comprises approximately 75% of breast biopsy diagnoses, performed following abnormal mammographic findings. Benign breast disease can be, based on Dupont and Page, classified into nonproliferative diseases such as fibroadenomas, cysts, microcalcifications, fibrosis, apocrine, metaplasia, atrophy, fatty tissue necrosis, inflammatory tissue and ectasia, or proliferative disease which includes scar, hyperplasia, sclerosing adenosis, papilloma, adenosis, intraductal hyperplasia, lobular hyperplasia, benign Phylloides tumor, benign mesenchymal tumors, epithelial benign tumors, atypia, atypical ductal hyperplasia, and lobular intraepithelial neoplasia. Surgical biopsy specimens diagnosed as nonproliferative disease, proliferative disease without atypia, or atypical ductal hyperplasia are associated with long term risk of breast cancer. However, there is limited knowledge on breast cancer risk associated with percutaneously diagnosed benign breast diseases.

The researchers conducted this retrospective cohort study to estimate breast cancer risk among women diagnosed with benign breast disease (BBD) through percutaneous biopsies from 2002 to 2013. The study included 4,819 women with a median age of 51 years. The participants were followed from 6 months after biopsy until breast cancer diagnosis, or December 2021. Researchers compared breast cancer risk for women with benign breast disease with the female breast cancer incidence rates obtained from the Iowa Surveillance, Epidemiology, and End Results (SEER) program. The Primary outcome was overall breast cancer diagnoses, as well as diagnoses stratified as Ductal Carcinoma In Situ (DCIS) or invasive breast cancer. About 79% of women underwent core biopsy only, 10% underwent core biopsy and surgical excision and 11% underwent excisional biopsy only. Based on the most severe lesion identified, 50.8% of biopsy specimens were nonproliferative, 42% were proliferative disease without atypia, and 7.2% were atypical hyperplasia.

It was noted that women with benign breast disease diagnosed by percutaneous biopsies had a significantly higher overall breast cancer risk compared to the general population (Standard Incidence Ratio [SIR] = 1.95).

(The SIR is an estimate of the number of cancer cases in a given population compared to what might be “expected” based on a comparison with the cancer experience in a larger population.)

Breast cancer risk increased with the severity of benign breast disease, with SIR = 1.42 for nonproliferative lesions, SIR = 2.19 for proliferative disease without atypia and SIR = 3.91 for atypical hyperplasia. This pattern was comparable to surgical cohorts with benign breast disease.

The risk of breast cancer also increased with the multiplicity of lesions. Women with three or more foci of nonproliferative lesions had an SIR of 2.40, proliferative disease without atypia had an SIR of 3.72, and atypical hyperplasia had an SIR of 5.29, all compared with the general population.

Women with benign breast disease had an increased risk for both invasive breast cancer (SIR = 1.56) and Ductal Carcinoma In Situ (DCIS) (SIR = 3.10), compared to the general population.

The 10-year cumulative breast cancer incidence was 4.3% for nonproliferative lesions, 6.6% for proliferative disease without atypia and 14.6% for atypical hyperplasia, compared with the expected population cumulative incidence of 2.9%.

It was concluded from this study that there is an increased breast cancer risk among women with benign breast diseases diagnosed through percutaneous biopsies. The findings from this study emphasize the importance of considering both the severity and multiplicity of benign breast disease lesions for improved breast cancer risk stratification. The authors also suggest that advancements in digital imaging and computational pathology approaches may enhance future analysis of benign breast disease biopsy specimens, for better risk prediction.

Benign Breast Disease and Breast Cancer Risk in the Percutaneous Biopsy Era. Sherman ME, Vierkant RA, Winham SJ, et al. JAMA Surg. 2024;159:193-201.

New ASCO Guideline Recommends Germline Testing in ALL Newly Diagnosed Breast Cancer Patients 65 Years or Younger

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.

The availability of multigene panel testing and next-generation sequencing can change the landscape of cancer prevention and treatment. However, there is lack of guidance for clinicians on whom to test and/or which genes to include in germline genetic testing panels for Pathogenic Variants.

The American Society of Clinical Oncology along with the Society of Surgical Oncology on January 4, 2024 provided new clinical practice guideline for clinicians and other Health Care Providers, regarding the role of germline mutation testing in patients with breast cancer, based on the best available evidence. These recommendations were developed based on a systematic review of 47 articles that met eligibility criteria for the germline mutation testing recommendations, and 18 articles that met eligibility criteria for the genetic counseling recommendations.

The guideline addressed the following question: Which patients with breast cancer should have germline genetic testing for Pathogenic Variants (PVs) in cancer susceptibility genes?

Question 1. Should clinicians offer BRCA1/2 testing to all patients with newly diagnosed breast cancer?
Recommendation 1.1
All patients newly diagnosed with breast cancer with Stage I-III or de novo Stage IV/metastatic disease who are 65 years or younger at diagnosis should be offered BRCA1/2 testing.
Recommendation 1.2
All patients newly diagnosed with breast cancer with Stage I-III or de novo Stage IV/metastatic disease who are older than age 65 should be offered BRCA1/2 testing if:
a) They are candidates for poly(ADP–ribose) polymerase (PARP) inhibitor therapy for early-stage or metastatic disease.
b) They have triple-negative breast cancer.
c) Their personal or family history suggests the possibility of a pathogenic variant.
d) They were assigned male sex at birth.
e) They are of Ashkenazi Jewish ancestry or are members of a population with an increased prevalence of founder mutations.
Recommendation 1.3
Patients undergoing BRCA1/2 testing should also be offered testing for other cancer predisposition genes as suggested by their personal or family history. Consultation with a provider experienced in clinical cancer genetics can help guide this decision-making and should be made available to patients when possible.

Question 2. Should all people with recurrent disease, local or metastatic, or with second breast primary, be offered BRCA1/2 testing?
Recommendation 2.1
All patients with recurrent breast cancer (local or metastatic) who are candidates for PARP inhibitor therapy should be offered BRCA1/2 testing regardless of family history.
Qualifying statement.
Small single-arm studies show that oral PARP inhibitor therapy demonstrates high response rates in women with metastatic breast cancer and germline pathogenic variants in PALB2.
Recommendation 2.2
BRCA1/2 testing should be offered to patients with a second primary cancer either in the contralateral or ipsilateral breast.

Question 3. Should people with a personal history of breast cancer (and no active disease) be offered BRCA1/2 testing?
Recommendation 3.1
All patients with a personal history of breast cancer diagnosed 65 years or less who are without active disease should be offered BRCA1/2 testing if the result will inform personal risk management or family risk assessment.
Recommendation 3.2
All patients with a personal history of breast cancer diagnosed over age 65 with no active disease, who meet one of the following criteria, should be offered BRCA1/2 testing if the result will inform personal risk management or family risk assessment:
a) Their personal or family history suggests the possibility of a pathogenic variant.
b) They were assigned male sex at birth.
c) They had triple-negative breast cancer.
d) They are of Ashkenazi Jewish ancestry or are members of a population with an increased prevalence of founder mutations.

Question 4. What is the value of testing patients with a diagnosis of breast cancer for breast cancer predisposition genes other than BRCA1/2?
Recommendation 4.1
Testing for high penetrance genes beyond BRCA1/2, including PALB2, TP53, PTEN, STK11, and CDH1, could inform medical therapy, influence surgical decision making, refine estimates of risks of second primary cancer, and inform family risk assessment, and thus should be offered to appropriate patients.
Recommendation 4.2
Testing for moderate penetrance breast cancer genes currently offers no benefits for treatment of the index breast cancer but may inform risks of second primary cancer or family risk assessment, and thus may be offered to appropriate patients who are undergoing BRCA1/2 testing.
Recommendation 4.3
If a multi-gene panel is ordered, the specific panel chosen should take into account the patients personal and family history. Consultation with a provider experienced in clinical cancer genetics can be helpful in selecting a specific multi-gene panel or interpreting its results and should be made available to patients when possible.

Question 5. How should patients with breast cancer considering genetic testing be counseled?
Recommendation 5.1
Patients undergoing genetic testing should be given sufficient information before testing to provide informed consent.
Recommendation 5.2
Patients with pathogenic variants should be provided with individualized post-test genetic counseling and offered referral to a provider experienced in clinical cancer genetics.
Recommendation 5.3
Variants of uncertain significance should not alter management. Patients should be made aware that variants of uncertain significance may be reclassified as being pathogenic, and they should understand that periodic follow up is necessary. Consultation with a provider experienced in clinical cancer genetics can be helpful and should be made available to patients when possible.
Recommendation 5.4
Patients without a pathogenic variant on genetic testing may still benefit from counseling, if there is a significant family history of cancer, and referral to a provider experienced in clinical cancer genetics is recommended.

ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care, and that all patients should have the opportunity to participate.

Germline Testing in Patients With Breast Cancer: ASCO–Society of Surgical Oncology Guideline. Bedrosian I, MD , Somerfield MR, PhD, Achatz MI, et al. J Clinical Oncol. 2024;42:584-604.

Omitting Axillary Lymph Node Dissection in Breast Cancer with Sentinel-Node Metastases

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.

Axillary lymph node status is a significant prognostic factor in patients with operable primary breast cancer, and is the most important predictor of recurrence and survival. Axillary lymph node dissection is used for staging of breast cancer and treatment of the axilla, if necessary. It is estimated that approximately 20-25% of women will have positive axillary lymph nodes when their breast cancer is detected through screening, whereas those with symptomatic early breast cancer have a 30-40% chance of having positive axillary nodes.

Axillary lymph node dissection is indicated for patients with proven axillary disease preoperatively or with a positive sentinel node biopsy. However, the landscape of breast cancer management has undergone significant evolution in recent years, particularly regarding the role of axillary surgery in node-negative disease. Among patients with clinically node negative breast cancer and 1-2 sentinel node metastases undergoing breast-conserving surgery and whole-breast radiation therapy, studies have shown that omission of axillary lymph node dissection did not have an impact on Overall Survival. However, questions remained about the necessity of completion axillary lymph node dissection in cases of sentinel-node metastases.

The SENOMAC trial was conducted in a large cohort of patients, to validate results from previous trials by comparing sentinel-node biopsy only with completion axillary lymph node dissection, in patients with clinically node-negative breast cancer and sentinel-lymph-node metastases. This study specifically focused only on patients with sentinel node macrometastases and extended eligibility criteria to include underrepresented subgroups such as those patients undergoing mastectomy, those with sentinel-node extracapsular extension or T3 tumors (tumor size more than 5 cm in the largest dimension), and men, thus broadening its applicability and relevance to real-world clinical scenarios.

In this ongoing, Phase III, international, randomized, non-inferiority trial which included 2540 patients (N=2540) from 5 European countries, 1335 had been assigned to undergo sentinel-node biopsy only with no further axillary surgery and 1205 to undergo completion axillary lymph node dissection (dissection group). Eligible patients had clinically node-negative breast cancer, with a tumor stage of T1, T2, or T3 (tumor size, T1, 2 cm or less; T2, 2-5 cm; and T3, more than 5 cm in greatest dimension) and one or two sentinel-node macrometastases (metastasis size, more than 2 mm in the greatest dimension). Patients who had suspicious but nonpalpable axillary lymph nodes on ultrasonography were eligible even if metastasis was confirmed by fine-needle aspiration. Adjuvant treatments and radiation therapy were administered in accordance with national guidelines, ensuring consistency in the approach to postoperative care across study participants. Whole-breast radiation therapy after breast-conserving surgery was mandatory, and radiation therapy including nodal target volumes was administered to 89.9% in the sentinel node biopsy-only group and to 88.4% in the dissection group. The median patient age was 61 yrs, approximately 64% had breast conserving surgery, 36% had mastectomy and 6% had T3 tumors. The Primary end point was Overall Survival (OS), and prespecified Secondary end points were Recurrence-Free Survival (RFS), Breast Cancer-Specific Survival, and Patient-Reported Outcomes. The median follow-up was 46.8 months.

Results from the trial demonstrated that the omission of completion axillary lymph node dissection was noninferior to the more extensive surgery in terms of Recurrence-Free Survival (RFS), and the estimated 5-year Recurrence-Free Survival was similar in the two treatment groups. The estimated 5-year RFS was 89.7% in the sentinel-node biopsy-only group and 88.7% in the dissection group, with a country-adjusted HR for recurrence or death of 0.89, which was significantly below the prespecified noninferiority margin (P<0.001).

These findings align with previous trials such as ACOSOG Z0011 and AMAROS, which also questioned the necessity of completion axillary lymph node dissection in certain patient populations. Yet, the SENOMAC trial offers distinct contributions. It included patients with T3 tumors and allowed for mastectomy, thus addressing gaps in previous research. Furthermore, the trial enrolled a substantial number of older patients, enhancing the generalizability of its results. Additionally, the trial adds to the growing body of evidence questioning the necessity of axillary surgery in diverse clinical scenarios, particularly in the era of advanced diagnostic imaging and tailored adjuvant therapies.

While the study has limitations, such as variations in radiation therapy practices and the predominantly luminal subtype of breast cancer among enrolled patients, its robust methodology and outcomes provide valuable insights. The results support the notion that axillary surgery may be unnecessary for certain patients with early-stage breast cancer and sentinel-node metastases, especially when combined with appropriate adjuvant therapies.

The researchers concluded that the omission of complete axillary lymph node dissection was noninferior to the more extensive surgery in patients with clinically node-negative breast cancer who had sentinel-node macrometastases, most of whom received nodal radiation therapy. The SENOMAC trial represents a significant milestone in advancing the evidence base and shaping clinical guidelines for the management of early-stage breast cancer with sentinel-node metastases.

Omitting Axillary Dissection in Breast Cancer with Sentinel-Node Metastases. de Boniface J, Tvedskov TF, Rydén L, et al. For the SENOMAC Trialists Group. N Engl J Med 2024;390:1163-1175.

Neoadjuvant KEYTRUDA® plus Chemotherapy Significantly Improves EFS in Early Stage High Risk Triple Negative Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. The American Cancer Society estimates that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.

Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients. It is usually aggressive, and tumors tend to be high grade and patients with TNBC are at a higher risk of both local and distant recurrence. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival (OS) of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers.

Neoadjuvant chemotherapy is the preferred treatment approach in this group of patients and can potentially increase the likelihood of tumor resectability and breast conservation. Further, a pathological Complete Response (pCR) after neoadjuvant chemotherapy can result in a longer Event-Free Survival and Overall Survival. Pathological Complete Response is therefore used as an end point for clinical testing of neoadjuvant treatment in patients with early triple-negative breast cancer.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response, and unleashes the tumor-specific effector T cells. The rationale for combining chemotherapy with immunotherapy is that cytotoxic chemotherapy releases tumor-specific antigens, and immune checkpoint inhibitors such as Pembrolizumab when given along with chemotherapy can enhance endogenous anticancer immunity. Single agent Pembrolizumab in metastatic TNBC demonstrated durable antitumor activity in several studies, with Objective Response Rates (ORRs) ranging from 10-21% and improved clinical responses in patients with higher PD-L1 expression. When given along with chemotherapy as a neoadjuvant treatment for patients with high-risk, early-stage TNBC, Pembrolizumab combination achieved pathological Complete Response rate of 65%, regardless of PD-L1 expression.

KEYNOTE-522 trial is a multicenter, randomized, double-blind, placebo-controlled Phase III trial, conducted to evaluate the efficacy and safety of neoadjuvant Pembrolizumab plus chemotherapy as compared with neoadjuvant placebo plus chemotherapy, followed by adjuvant Pembrolizumab or placebo in patients with early stage, high-risk, Triple Negative Breast Cancer. In this study, total of 1174 patients (N=1174) regardless of tumor PD⁠-⁠L1 expression, were randomly assigned 2:1 to receive Pembrolizumab plus chemotherapy (N=784) or placebo plus chemotherapy (N=390). Eligible patients had newly diagnosed, previously untreated, Triple Negative Breast Cancer, with tumor size more than 1 cm but 2 cm or less in diameter with nodal involvement, or tumor size more than 2 cm in diameter regardless of nodal involvement. Patients in the neoadjuvant phase received four cycles of Pembrolizumab 200 mg IV or placebo once every 3 weeks plus Paclitaxel 80 mg/m2 once weekly plus Carboplatin AUC 5 IV once every 3 weeks or Carboplatin AUC 1.5 IV once weekly in the first 12 weeks (first neoadjuvant treatment), followed by four cycles of Pembrolizumab or placebo along with Doxorubicin 60 mg/m2 IV or Epirubicin 90 mg/m2 IV plus Cyclophosphamide 600 mg/m2 IV once every 3 weeks in the subsequent 12 weeks (second neoadjuvant treatment). Patients then underwent definitive surgery (breast conservation or mastectomy with sentinel lymph-node evaluation or axillary dissection) 3-6 weeks after the last cycle of the neoadjuvant phase. In the adjuvant phase, patients received radiation therapy as indicated and Pembrolizumab or placebo once every 3 weeks for up to nine cycles. Adjuvant Capecitabine was not allowed. The median age was 49 yrs, 64% were white, 56% were premenopausal, and overall 75% had Stage II disease and 25% had Stage III disease. Both treatment groups were well balanced with regard to age, ECOG performance status, PD-L1-positivity, tumor size and nodal involvement. The Primary end points were a pathological Complete Response (pCR) at the time of definitive surgery and Event-Free Survival (EFS) in the intent-to-treat population. Pathological Complete Response was defined as absence of invasive cancer in the breast and lymph nodes (ypT0/Tis ypN0), and was assessed by the blinded local pathologist at the time of definitive surgery. EFS was defined as the time from randomization to the first occurrence of progression of disease that precludes definitive surgery, local or distant recurrence, second primary malignancy, or death due to any cause.

The pathological Complete Response rate was 63% in the Pembrolizumab plus chemotherapy group and 55.6% in the placebo plus chemotherapy group, and this difference were statistically significant. The EFS after median follow up of 63.1 months showed a 5-year EFS rate of 81.3% with Pembrolizumab plus chemotherapy and 72.3% with placebo plus chemotherapy (HR=0.63). The median EFS had not been reached in either group. The EFS benefit appeared consistent across subgroups, including those assessed by nodal status, disease stage, PD-L1 expression, menopausal status and Carboplatin schedule. A prespecified, exploratory analysis showed higher 5-year EFS rates with Pembrolizumab among patients who achieved pathologic Complete Response (92.2% versus 88.2%) and among those who did not achieve pathologic Complete Response (62.6% versus 52.3%).

It was concluded that the addition of Pembrolizumab with neoadjuvant chemotherapy followed by Pembrolizumab monotherapy in the adjuvant setting resulted in a durable Event Free Survival benefit, for patients with early stage Triple Negative Breast Cancer, and this benefit was noted across key subgroups, as well as among patients who did or did not achieve pathologic Complete Response.

Neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for early-stage triple-negative breast cancer: updated event-free survival results from the phase 3 KEYNOTE-522 study. Schmid P, Cortés J, Dent R, et al. Presented at the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX; abstract LBO1-01.

Pregnancy after Breast Cancer Treatment in BRCA Carriers

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.

The median age at the time of breast cancer diagnosis in the US is 62 years. However approximately 5% of new diagnoses each year occur in those who are under 40 years. These young patients with Hormone Receptor (HR)-positive breast cancer receiving modern adjuvant endocrine therapy have excellent long-term outcomes. Nonetheless, 40-60% of patients who are diagnosed with breast cancer at age 40 or younger are concerned about their future fertility and pregnancy, as many have not completed their family planning at diagnosis due to delay in childbearing. The POSITIVE (Pregnancy Outcome and Safety of Interrupting Therapy for Women with Endocrine Responsive Breast Cancer) trial designed to evaluate whether temporary interruption of adjuvant endocrine therapy to attempt pregnancy was associated with a higher risk of breast cancer recurrence, did indeed suggest that women with a history of HR-positive breast cancer could safely pause hormonal therapy to have a child. (N Engl J Med 2023; 388:1645-1656)

Young women diagnosed with breast cancer, especially those harboring a BRCA mutation, often desire to conceive post-treatment. However, concerns loomed over the safety of pregnancy following a breast cancer diagnosis. Previous studies provided limited data, necessitating further exploration to guide patients and physicians adequately.

This international Hospital-Based Cohort Study was conducted to investigate if pregnancy after breast cancer among women carrying germline BRCA pathogenic variants was associated with adverse maternal or fetal outcomes. The study encompassed a vast cohort comprising 4,732 women with a BRCA mutation, all diagnosed with invasive breast cancer at the age of 40 or younger, between January 2000 and December 2020. This extensive retrospective cohort study spanned numerous international hospital centers, ensuring a diverse and comprehensive representation of patients. The Primary end points of this study were cumulative incidence of pregnancy after breast cancer and Disease Free Survival (DFS). Secondary end points included Breast Cancer–Specific Survival, Overall Survival, pregnancy, fetal and obstetric outcomes. The median follow up was 7.8 years.

Out of the entire cohort of 4,732 women with a BRCA mutation, 659 patients had at least 1 pregnancy after their breast cancer diagnosis. The cumulative pregnancy incidence at 10 years after diagnosis was 22%. The median time from breast cancer diagnosis to conception was 3.5 years, and 28% of pregnancies occurred after 5 years. Compared with women who did not get pregnant, women who became pregnant were more likely to have a BRCA1 mutation alone (73% versus 63%), be younger at breast cancer diagnosis (median age 30 yrs versus 35 yrs), have node-negative disease (62.5% versus 52%), and have HR-negative disease (68% versus 52%).

The cumulative incidence of pregnancy at 10 years was 18% in patients with HR-positive disease and 26% in patients with HR-negative disease (P<0.001) and the median time from diagnosis to conception was 4.3 years and 3.2 years, respectively (P<0.001). The proportion of pregnancies occurring after 5 years was 40% and 22%, respectively.

Overall, the median age at pregnancy was 35 years, 79% of patients had a spontaneous pregnancy without the use of any assisted reproductive technology, and 80% delivered a child. Of all pregnancies, 8% had an induced abortion and 10% had a miscarriage, and majority of patients (86%) did not experience pregnancy complications. There was no significant difference in Disease Free Survival observed between patients with or without a pregnancy after breast cancer, and patients who had a pregnancy had significantly better Breast Cancer–Specific Survival and Overall Survival.

The authors from this study concluded that 1 in 5 young BRCA carriers conceived within 10 years after breast cancer diagnosis. They added that pregnancy following breast cancer in BRCA carriers was not associated with decreased Disease Free Survival and conceiving after proper treatment and follow up for breast cancer should not be contraindicated anymore in young BRCA carriers. Coupled with the analysis from the POSITIVE trial, which suggests that fertility preservation and assisted reproductive technologies do not heighten the risk of recurrence, these results alleviate many concerns surrounding post-breast cancer pregnancy.

This international, large-scale study offers critical insights into the safety and feasibility of pregnancy post-breast cancer diagnosis, for women with BRCA mutations. The findings provide valuable guidance for patients and healthcare providers, potentially reshaping clinical practices and decision-making processes. In essence, this pioneering research represents a pivotal milestone in the field of breast cancer management, offering hope, reassurance, and clarity to countless young women navigating the intersection of cancer treatment and fertility preservation.

Pregnancy After Breast Cancer in Young BRCA Carriers. Lambertini M, Blondeaux E, Agostinetto E, et al. JAMA. 2024;331:49-59.

Avoiding Regional Nodal Irradiation after Neoadjuvant Chemotherapy in Some Breast Cancer Patients

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.

Neoadjuvant or preoperative therapy is often a component of combined-modality treatment, and facilitates the rapid assessment of new cancer therapies. In addition to increasing the likelihood of tumor resectability and breast preservation, patients achieving a pathological Complete Response (pCR) following neoadjuvant chemotherapy have a longer Event Free Survival (EFS) and Overall Survival (OS).

When patients with early stage breast cancer present with pathologically positive axillary nodes, neoadjuvant chemotherapy is often recommended to eradicate cancer cells. These patients are often treated with adjuvant regional nodal irradiation including the chest wall after mastectomy and with whole breast irradiation after breast conserving surgery.

However, there is no established protocol for treatment when chemotherapy converts node-positive disease to node-negative disease. There is an ongoing debate whether these individuals should be treated as lymph node-positive disease (as it was at the time of diagnosis) and treated with radiation treatment, or as node-negative disease (presentation after neoadjuvant chemotherapy and following surgery). Radiation Therapy can be associated with fatigue, radiation dermatitis, lymphedema, and can have an impact on breast reconstruction. The following study was conducted to evaluate whether radiation treatment can be safely omitted in this patient population

The NRG Oncology/NSABP B-51/RTOG 1304 was conducted to evaluate the impact of Regional Nodal Irradiation (RNI) on patient outcomes following neoadjuvant chemotherapy. In this Phase III clinical trial, 1,641 enrolled patients had clinical cT1-3, N1, M0 invasive breast cancer (biopsy-proven node positive by FNA/core needle bx), and had completed 8 weeks or more of neoadjuvant chemotherapy and anti-HER2 therapy if HER2-positive), and were ypN0 after mastectomy or breast conserving surgery and sentinel node biopsy (2 or more nodes), axillary lymph node dissection, or both. These patients were then randomly assigned 1:1 to either the “no RNI” group (observation after mastectomy, or whole breast irradiation after breast-conserving surgery) or the “RNI” group (chest wall irradiation plus RNI after mastectomy, or whole breast irradiation plus RNI after breast-conserving surgery). Both treatment groups were well balanced. The median age was 52 years, majority of the patients (60%) were cT2, 23% were triple-negative, 21% HR+/HER2-negative, 56% were HER2-positive and 78% had breast pathologic Complete Response. The Primary endpoint was Invasive Breast Cancer Recurrence-Free Interval (IBC-RFI). Secondary endpoints reported here included Loco-Regional Recurrence-Free interval (LRRFI), Distant Recurrence-Free Interval (DRFI), Disease-Free Survival (DFS), and Overall Survival (OS). The median follow up was 59.5 months and 1,556 patients were available for primary event analysis.

In the evaluable patients (N=1556), similar outcomes were noted whether the patients received adjuvant Regional Nodal Irradiation (RNI) or not. Approximately 92% of patients in the “no RNI” group and 92.7% of those in the “RNI” group were free of Invasive Breast Cancer Recurrences five years after surgery. Distant Recurrence and Overall Survival rates were also similar between the treatment groups, with 93.4% of patients in each treatment group free from Distant Recurrence five years after surgery, and 94% of those in the “no RNI” group and 93.6% of those in the “RNI” group alive after five years. There were no study-related deaths and no unexpected toxicities.

It was concluded from this study that certain breast cancer patients who respond well to neoadjuvant chemotherapy and achieve negative lymph nodes after surgery may safely omit adjuvant lymph node radiation without compromising outcomes. If confirmed by further research and endorsed by medical guidelines, these findings could spare many breast cancer patients from unnecessary radiation therapy, thereby reducing treatment-related side effects and improving quality of life. This study underscores the importance of individualized treatment approaches in oncology, highlighting the need to reassess treatment strategies based on evolving evidence.

Loco-regional irradiation in patients with biopsy-proven axillary node involvement at presentation who become pathologically node-negative after neoadjuvant chemotherapy: Mamounas E, Bandos H, White J, et al: Primary outcomes of NRG Oncology/NSABP B-51/RTOG 1304. 2023 San Antonio Breast Cancer Symposium. Abstract GS02-07. Presented December 7, 2023.

TRUQAP® (Capivasertib)

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The FDA on November 16, 2023, approved TRUQAP® with Fulvestrant for adult patients with hormone receptor (HR)-positive, Human Epidermal growth factor Receptor 2 (HER2)-negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alterations, as detected by an FDA-approved test, following progression on at least one endocrine-based regimen in the metastatic setting, or recurrence on or within 12 months of completing adjuvant therapy. TRUQAP® is a product of AstraZeneca Pharmaceuticals.

New ASCO Guideline Recommends Germline Testing in ALL Newly Diagnosed Breast Cancer Patients 65 Years or Younger

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.

The availability of multigene panel testing and next-generation sequencing can change the landscape of cancer prevention and treatment. However, there is lack of guidance for clinicians on whom to test and/or which genes to include in germline genetic testing panels for Pathogenic Variants.

The American Society of Clinical Oncology along with the Society of Surgical Oncology on January 4, 2024 provided new clinical practice guideline for clinicians and other Health Care Providers, regarding the role of germline mutation testing in patients with breast cancer, based on the best available evidence. These recommendations were developed based on a systematic review of 47 articles that met eligibility criteria for the germline mutation testing recommendations, and 18 articles that met eligibility criteria for the genetic counseling recommendations.

The guideline addressed the following question: Which patients with breast cancer should have germline genetic testing for Pathogenic Variants (PVs) in cancer susceptibility genes?

Question 1. Should clinicians offer BRCA1/2 testing to all patients with newly diagnosed breast cancer?
Recommendation 1.1
All patients newly diagnosed with breast cancer with Stage I-III or de novo Stage IV/metastatic disease who are 65 years or younger at diagnosis should be offered BRCA1/2 testing.
Recommendation 1.2
All patients newly diagnosed with breast cancer with Stage I-III or de novo Stage IV/metastatic disease who are older than age 65 should be offered BRCA1/2 testing if:
a) They are candidates for poly(ADP–ribose) polymerase (PARP) inhibitor therapy for early-stage or metastatic disease.
b) They have triple-negative breast cancer.
c) Their personal or family history suggests the possibility of a pathogenic variant.
d) They were assigned male sex at birth.
e) They are of Ashkenazi Jewish ancestry or are members of a population with an increased prevalence of founder mutations.
Recommendation 1.3
Patients undergoing BRCA1/2 testing should also be offered testing for other cancer predisposition genes as suggested by their personal or family history. Consultation with a provider experienced in clinical cancer genetics can help guide this decision-making and should be made available to patients when possible.

Question 2. Should all people with recurrent disease, local or metastatic, or with second breast primary, be offered BRCA1/2 testing?
Recommendation 2.1
All patients with recurrent breast cancer (local or metastatic) who are candidates for PARP inhibitor therapy should be offered BRCA1/2 testing regardless of family history.
Qualifying statement.
Small single-arm studies show that oral PARP inhibitor therapy demonstrates high response rates in women with metastatic breast cancer and germline pathogenic variants in PALB2.
Recommendation 2.2
BRCA1/2 testing should be offered to patients with a second primary cancer either in the contralateral or ipsilateral breast.

Question 3. Should people with a personal history of breast cancer (and no active disease) be offered BRCA1/2 testing?
Recommendation 3.1
All patients with a personal history of breast cancer diagnosed 65 years or less who are without active disease should be offered BRCA1/2 testing if the result will inform personal risk management or family risk assessment.
Recommendation 3.2
All patients with a personal history of breast cancer diagnosed over age 65 with no active disease, who meet one of the following criteria, should be offered BRCA1/2 testing if the result will inform personal risk management or family risk assessment:
a) Their personal or family history suggests the possibility of a pathogenic variant.
b) They were assigned male sex at birth.
c) They had triple-negative breast cancer.
d) They are of Ashkenazi Jewish ancestry or are members of a population with an increased prevalence of founder mutations.

Question 4. What is the value of testing patients with a diagnosis of breast cancer for breast cancer predisposition genes other than BRCA1/2?
Recommendation 4.1
Testing for high penetrance genes beyond BRCA1/2, including PALB2, TP53, PTEN, STK11, and CDH1, could inform medical therapy, influence surgical decision making, refine estimates of risks of second primary cancer, and inform family risk assessment, and thus should be offered to appropriate patients.
Recommendation 4.2
Testing for moderate penetrance breast cancer genes currently offers no benefits for treatment of the index breast cancer but may inform risks of second primary cancer or family risk assessment, and thus may be offered to appropriate patients who are undergoing BRCA1/2 testing.
Recommendation 4.3
If a multi-gene panel is ordered, the specific panel chosen should take into account the patients personal and family history. Consultation with a provider experienced in clinical cancer genetics can be helpful in selecting a specific multi-gene panel or interpreting its results and should be made available to patients when possible.

Question 5. How should patients with breast cancer considering genetic testing be counseled?
Recommendation 5.1
Patients undergoing genetic testing should be given sufficient information before testing to provide informed consent.
Recommendation 5.2
Patients with pathogenic variants should be provided with individualized post-test genetic counseling and offered referral to a provider experienced in clinical cancer genetics.
Recommendation 5.3
Variants of uncertain significance should not alter management. Patients should be made aware that variants of uncertain significance may be reclassified as being pathogenic, and they should understand that periodic follow up is necessary. Consultation with a provider experienced in clinical cancer genetics can be helpful and should be made available to patients when possible.
Recommendation 5.4
Patients without a pathogenic variant on genetic testing may still benefit from counseling, if there is a significant family history of cancer, and referral to a provider experienced in clinical cancer genetics is recommended.

ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care, and that all patients should have the opportunity to participate.

Germline Testing in Patients With Breast Cancer: ASCO–Society of Surgical Oncology Guideline. Bedrosian I, MD , Somerfield MR, PhD, Achatz MI, et al. Journal of Clinical Oncology January 04, 2024. https://doi.org/10.1200/JCO.23.02225.

Neoadjuvant Chemoimmunotherapy Improves Pathologic Complete Response Rates in Early Stage ER-Positive, HER2-Negative Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor (HR)-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. Approximately 25% of patients with early-stage breast cancer who receive (neo)adjuvant chemotherapy experience a recurrence within 5 years (Lancet Oncol. 2018;19:27-39).

The promising efficacy observed with single-agent checkpoint blockade for advanced HER2-negative breast cancer, and the significant benefit observed with PD-1 inhibitors combined with chemotherapy for lung cancer and other cancer types, led the researchers to evaluate the efficacy of adding Pembrolizumab to standard neoadjuvant chemotherapy. In the Phase 2 I-SPY2 trial, Pembrolizumab plus neoadjuvant chemotherapy improved estimated pathological Complete Response rates versus neoadjuvant chemotherapy alone, at 30% versus 13%, in patients with HR-positive, HER2-negative breast cancer.

Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. The rationale for combining chemotherapy with immunotherapy is that cytotoxic chemotherapy releases tumor-specific antigens, and immune checkpoint inhibitors such as Pembrolizumab when given along with chemotherapy can enhance endogenous anticancer immunity.

Pembrolizumab is approved for the treatment of patients with high-risk early-stage Triple Negative Breast Cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, as well as in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS 10 or more).

KEYNOTE-756 is a global, randomized, double-blind, Phase III trial, conducted to assess the efficacy and safety of Pembrolizumab versus placebo, in combination with neoadjuvant chemotherapy followed by adjuvant treatment with Pembrolizumab plus endocrine therapy, in adults with high-risk, early stage ER-positive HER2- negative breast cancer. In this study 1,278 enrolled patients (N=1278) were randomized 1:1 to receive Pembrolizumab 200 mg IV ever 3 weeks or placebo, both given with Paclitaxel weekly for 12 weeks, followed by 4 additional cycles of Doxorubicin or Epirubicin plus Cyclophosphamide (neoadjuvant treatment) prior to surgery. Following definitive surgery with or without radiation treatment, patients received Pembrolizumab or placebo every 3 weeks for 9 cycles plus endocrine therapy for up to 10 years, as adjuvant therapy post-surgery. Eligible patients had centrally confirmed T1c-2 (≥2 cm) cN1-2 or T3-4 cN0-2, Grade 3, ER-positive, HER2-negative, invasive ductal carcinoma, and were treatment-naive. Both treatment groups were well balanced. The median age was 49 years, about 76% of patients in each treatment group had a PD-L1 CPS of 1 or higher, about 40% had a CPS of 10 or higher, and about 90% had nodal involvement. About 62% of patients had Stage II disease, and 38% had Stage III disease. The dual Primary endpoints were pathological Complete Response (pCR) rate (ypT0/Tis ypN0), defined as absence of invasive cancer in the breast and axillary lymph nodes at the time of surgery, and Event Free Survival (EFS). Secondary endpoints included Overall Survival and Safety.

With a median follow-up of 33.2 months, the study demonstrated a statistically significant improvement in pCR rates with Pembrolizumab compared to placebo. The pCR rate in the intention-to-treat (ITT) population was 24.3% with Pembrolizumab versus 15.6% with placebo (absolute difference 8.5%; P = 0.00005). Similar improvements were observed across various subgroups, including patients with Stage II or III disease, positive lymph nodes at baseline, and higher PD-L1 expression levels. Pembrolizumab demonstrated superior efficacy across geographic regions and exhibited a linear improvement in pCR rates with increasing PD-L1 expression.

Further analyses showed a greater pCR benefit with Pembrolizumab in patients with low estrogen receptor (ER) positivity (defined as less than 10% of ER-positive cells), node positive disease and those with higher PD-L1 expression. Pembrolizumab recipients who received full-dose chemotherapy had a greater pCR benefit compared to those who received reduced chemotherapy doses. Additionally, Pembrolizumab recipients were more likely to shift to lower Residual Cancer Burden (RCB) groups post-surgery. The trial also observed higher rates of immune-mediated adverse events with Pembrolizumab compared to placebo, with common events including hypothyroidism, hyperthyroidism, and pneumonitis.

It was concluded from this study that, the addition of Pembrolizumab to neoadjuvant chemotherapy followed by adjuvant Pembrolizumab plus endocrine therapy, significantly improves pCR rates in patients with early stage, high risk ER-positive, HER2-negative breast cancer. Further assessment of long term outcomes, including Event-Free Survival and Overall Survival is ongoing to fully evaluate the clinical benefit of this treatment approach. The study sponsors added that this is the first positive Phase III study, evaluating an immunotherapy-based regimen for patients with high risk, early stage ER-positive, HER2-negative breast cancer, and an important milestone in advancing research, in early stage breast cancer.

Phase 3 study of neoadjuvant pembrolizumab or placebo plus chemotherapy, followed by adjuvant pembrolizumab or placebo plus endocrine therapy for early-stage high-risk ER+/HER2- breast cancer: KEYNOTE-756. Cardoso F, O’Shaughnessy J, McArthur H, et al. Presented at SABCS 2023. December 5-9, 2023. San Antonio, TX. Abstract GS01-02.