Tag: Breast Cancer

Unfulfilled Potential: The Gap in Genetic Testing for 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. 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.

The availability of multigene panel testing and next-generation sequencing is changing the landscape of cancer prevention and treatment. The necessity for genetic testing in breast cancer has gained support due to its critical role in treatment management and family risk assessment. Clinical guidelines have evolved to expand eligibility for genetic testing, yet many patients who could benefit from these tests either do not receive them or face delays in testing. This is concerning, as genetic testing informs treatment decisions, surveillance for second cancers, and risk management for relatives. This present study aimed to explore the receipt of genetic testing and communication with relatives about results in women diagnosed with early-stage breast cancer, examining patterns from initial diagnosis through survivorship, a time that is often overlooked for its importance in continued care. Specifically, it aimed to assess how these factors influence survivorship and familial risk communication over time.

The study utilized a cohort of women aged 20-79 years diagnosed with early-stage breast cancer in 2014-2015, sourced from the Georgia and Los Angeles County SEER registries. A total of 1,412 women were surveyed approximately 7 months after diagnosis and again 6 years later. The surveys collected data on genetic counseling, testing, and communication about test results. Participants were categorized based on clinical guidelines into three groups:
• Indications at Baseline: Women who had indications for genetic testing at the time of initial diagnosis.
• Indications at Follow-up Only (FUPs): Women who had indications for testing only during follow-up.
• No Indications: Women who did not have indications for genetic testing at any point.

The findings revealed that nearly half (47.4%) of the women had indications for genetic testing at some point- 28.0% at baseline and an additional 19.4% during follow-up. Among those who had an indication at baseline, 71.9% reported having undergone genetic testing. This rate was significantly higher compared to those with an indication only at follow-up (53.3%) and those with no indication (35.0%). Statistical analysis showed significant differences in testing rates between these groups (P<0.001). Importantly, racial and ethnic differences did not significantly affect the receipt of testing when controlling for age and clinical indications (P=0.239). The results for genetic counseling were similar.

Only a small fraction (3.4%) of the women pursued Direct-to-Consumer genetic testing (DTCt) for cancer.

Women who tested positive for a Pathogenic Variant (N = 62) were significantly more likely to discuss their results with most or all of their first-degree relatives compared to those with a Variant of Unknown Significance (N = 49) or a negative result (N = 419). Specifically, 62.7% of women with Pathogenic Variants communicated results to their relatives, compared to those with a Variant of Unknown Significance (38.8%) or a negative result (38.0%), (P<0.001).

In conclusion, this study underscores a significant gap in the uptake of genetic counseling and testing among women who are eligible for it based on clinical guidelines. While the proportion of women with indications for genetic testing increased over time, many women did not receive it. This gap was consistent across racial and ethnic groups, suggesting that the issue is widespread rather than confined to specific subpopulations. The study emphasizes that positive genetic results lead to increased family communication about cancer risk, whereas the uptake of DTCt remains low, reaffirming its limited role in replacing clinical-grade genetic testing in this population.

Genetic Counseling, Testing, and Family Communication Into Survivorship After Diagnosis of Breast Cancer. Katz SJ, Abrahamse P, Furgal A, et al. J Clin Oncol. 2024;doi:10.1200/JCO.24.00122.

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.

Late Breaking Abstract – ASCO 2024: Docetaxel may be Preferable Taxane for Black Women to Mitigate Taxane-Induced Peripheral Neuropathy

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SUMMARY: Taxane-induced peripheral neuropathy (TIPN) is a notable side effect associated with taxane chemotherapy agents, particularly Paclitaxel, and has significant implications for patient quality of life and treatment outcomes. Notably, Black women with early-stage breast cancer exhibit a disproportionately higher incidence of TIPN compared to their White counterparts. This disparity is critical, as TIPN can lead to increased dose reductions, which in turn may adversely affect treatment efficacy and long-term cure rates.

Historically, retrospective analyses, such as those from the ECOG-ACRIN-E5103 trial, revealed that Black patients experience more severe TIPN and subsequent dose reductions when treated with weekly Paclitaxel. This pattern was less pronounced in patients treated with every 3 week Docetaxel. Additionally, genetic studies identified specific germline variants associated with a heightened risk of severe TIPN in individuals of African ancestry. These findings prompted the need for a prospective trial to validate these genetic markers and to evaluate the comparative tolerability of Paclitaxel versus Docetaxel specifically in Black women.

The EAZ171 study was designed with several key objectives. It aimed to prospectively validate whether specific germline genetic variants are associated with a higher risk of TIPN in Black women. The focus was on genetic variants in the SBF2 and FCAMR genes. The Secondary objective of this study was to compare the incidence of TIPN and the frequency of dose reductions between two taxanes—weekly Paclitaxel and every 3 week Docetaxel, in a cohort of Black women with early-stage breast cancer.

This study included 249 Black women who self-identified as such and were scheduled to receive either Paclitaxel 80 mg/m² IV weekly for 12 doses (N=121) or Docetaxel 75 mg/m² IV every 3 weeks for 4-6 cycles (N=128). The study utilized a pragmatic design where the choice of taxane was based on physician discretion and patient-specific disease characteristics, rather than a randomized design. Patients could also receive Cyclophosphamide, Doxorubicin, Trastuzumab, and/or Pertuzumab per institution routine care, per treating physician discretion. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Participants were genotyped to identify genetic variants associated with neuropathy risk. Those with FCAMR homozygous wild type or SBF2 mutations were categorized as high risk, while those with variant alleles in FCAMR and wild type SBF2 were categorized as low risk. The incidence of Grade 2-4 TIPN was evaluated using physician-reported CTCAE v.5, while patient-reported outcomes were assessed through PRO-CTCAE, FACT/GOG-NTx, and EORTC CIPN20 questionnaires.

The key findings were:

Genetic Predictors: Germline variations did not significantly influence the risk of TIPN for either treatment group. The anticipated differences in TIPN based on genetic risk did not reach statistical significance.

TIPN Incidence: Grade 2-4 TIPN was notably higher in the Paclitaxel group compared to the Docetaxel group. Physician-reported TIPN was 45% in the Paclitaxel arm versus 29% in the Docetaxel arm (P=0.02). Similarly, patient-reported TIPN symptoms were 40% with Paclitaxel versus 24% with Docetaxel (P=0.03).

Dose Reductions: Patients receiving Paclitaxel experienced more frequent dose reductions due to TIPN (28% vs. 9%, p<0.001) and for any cause (39% vs. 25%, p=0.02) compared to those receiving Docetaxel.

Patient-Reported Outcomes: The trends in worsening neuropathy scores over time were similar between the two arms, but significant differences were not observed at the one-year mark.

In summary, the EAZ171 study provided crucial insights into the management of TIPN in Black women with early-stage breast cancer. Despite the lack of significant impact from genetic markers, the clear advantage of Docetaxel over Paclitaxel in terms of lower incidence of severe TIPN and fewer dose reductions underscores its potential as a preferable taxane for this patient population. This trial results advocate for considering Docetaxel in treatment regimens for Black women to mitigate TIPN-related complications and possibly enhance treatment outcomes. The findings emphasize the need for tailored treatment strategies to improve health equity and therapeutic efficacy in breast cancer care.

ECOG-ACRIN EAZ171: Prospective validation trial of germline variants and taxane type in association with taxane-induced peripheral neuropathy (TIPN) in Black women with early-stage breast cancer. Ballinger TJ, Zhao F, Sparano JA, et al. J Clin Oncol 42, 2024 (suppl 17; abstr LBA503). DOI: 10.1200/JCO.2024.42.17_suppl.LBA503

Late Breaking Abstract – ASCO 2024: Switching to VERZENIO® Post-CDK4/6 inhibitor Progression May Improve Outcomes in HR-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. These patients are often treated with single agent endocrine therapy, endocrine therapy in combination with CDK4/6 inhibitor, or single agent chemotherapy.

Cyclin Dependent Kinases (CDK) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. Cyclin Dependent Kinases 4 and 6 (CDK4 and CDK6) phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity and phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in hormone receptor positive breast cancer, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation and associated with increased expression of CDK4. The understanding of the role of Cyclin Dependent Kinases in the cell cycle, has paved the way for the development of CDK inhibitors.

Abemaciclib (VERZENIO®) is an oral, selective inhibitor of CDK4 and CDK6 kinase activity that prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation. Abemaciclib is structurally distinct from other CDK 4 and 6 inhibitors (such as Ribociclib and Palbociclib) and is 14 times more potent against cyclin D1/CDK 4 and cyclin D3/CDK 6, in enzymatic assays, but potentially less toxic than earlier pan-CDK inhibitors. At higher doses, only Abemaciclib causes significant cancer cell death, compared with other CDK4/6 inhibitors, suggesting that this drug may be affecting proteins, other than CDK4/6. Additionally, preclinical studies have demonstrated that Abemaciclib may have additional therapeutic benefits for a subset of tumors that are unresponsive to treatment or have grown resistant to other CDK4/6 inhibitors.

For the patient group with advanced or metastatic HR-positive, HER2-negative breast cancer, Abemaciclib has FDA approval in combination with an Aromatase Inhibitor as initial endocrine-based therapy, in combination with Fulvestrant, with disease progression following endocrine therapy, and as monotherapy with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. Abemaciclib has activity in the Central Nervous System, and is included in the ASCO guidelines among the active agents in ER-positive/HER2-amplified breast cancer with brain metastasis. Abemaciclib has been shown to be an effective therapy after treatment with Palbociclib, another CDK4/6 inhibitor.

postMONARCH is a global, randomized, double-blind, placebo-controlled Phase III trial conducted to evaluate the efficacy and safety of Abemaciclib in combination with Fulvestrant compared to a placebo plus Fulvestrant in patients with HR-positive/HER2-negative advanced breast cancer, who experienced disease progression on a prior CDK4/6 inhibitor plus endocrine therapy. In this study, 368 patients (N=368) were randomized in a 1:1 ratio to receive either Abemaciclib plus Fulvestrant (N=182) or placebo plus Fulvestrant (N=186). The eligibility criteria included disease progression on a CDK4/6 inhibitor plus Aromatase Inhibitor as initial therapy for advanced disease, or relapse on or after CDK4/6 inhibitor plus endocrine therapy as adjuvant therapy for early breast cancer. No prior treatment for advanced disease aside from the initial regimen was allowed. The majority (99%) had progressed on a CDK4/6 inhibitor plus endocrine therapy as initial therapy for advanced disease. Prior CDK4/6 inhibitor treatments included Palbociclib (59%), Ribociclib (33%), and Abemaciclib (8%). Approximately 99% of patients had progressed on CDK4/6 inhibitor plus endocrine therapy as initial treatement for advanced breast cancer. The two treatment groups were well balanced. The median age was 59 years and stratification factors included duration of prior CDK4/6 inhibition, visceral metastases, and geographic region. Approximately 60% of patients had visceral metastasis and Imaging studies were performed every 8 weeks for the first 12 months and then every 12 weeks. The Primary endpoint was investigator-assessed Progression Free Survival (PFS). Secondary endpoints encompassed PFS assessed by Blinded Independent Central Review (BICR), Overall Survival (OS), Objective Response Rate (ORR), and Safety. The study analysis was event-driven, with the primary outcome targeting 258 events, and with an interim analysis planned at 70% of events.

At the interim analysis, with 70% of the planned events, Abemaciclib plus Fulvestrant demonstrated a statistically significant improvement in investigator-assessed PFS compared to placebo plus Fulvestrant (HR=0.66; P=0.01). Upon completion of the primary analysis with 258 events, the HR for PFS was 0.73 reflecting a 27% reduction in the risk of disease progression or death. The 6-month PFS rates were 50% for the Abemaciclib group versus 37% for the placebo group. The benefit of Abemaciclib was more pronounced with BICR-assessed PFS, showing a HR of 0.55 representing a 45% reduction in the risk of disease progression or death. In patients with measurable disease, the ORR was 17% for the Abemaciclib group compared to 7% for the placebo group (P=0.0145 by investigator assessment and P=0.0008 by BICR). OS data remained immature with a 20.9% event rate at the time of analysis.

Subgroup Analyses suggested that patients with prior CDK4/6 inhibitor use for more than 12 months had a median PFS of 7.0 months versus 5.4 months in the placebo group (HR=0.70; 95% CI = 0.52–0.94). For those with treatment durations up to 12 months, the median PFS was 5.5 months versus 3.0 months (HR=0.80; 95% CI = 0.50–1.29). The benefit was greater in patients without visceral metastases (HR=0.53; 95% CI = 0.34–0.83), though there was still a benefit observed in those with visceral metastases (HR=0.87; 95% CI = 0.64–1.17). Benefit was observed regardless of presence of ESR1 mutations or PI3K pathway alterations.

The safety profile of Abemaciclib plus Fulvestrant was consistent with known profiles. Grade 3 neutropenia occurred in 25% of patients receiving the combination therapy. Adverse events led to discontinuation in 6% of patients on the Abemaciclib arm, compared with none in the placebo group. The most common Grade 3 or higher adverse events included neutropenia, anemia, and leukopenia.

In summary, the postMONARCH trial supports the use of Abemaciclib plus Fulvestrant as an effective treatment for patients with HR-positive/HER2-negative advanced breast cancer who have progressed on prior CDK4/6 inhibitor plus endocrine therapy, offering a viable option and underscoring the value of continued CDK4/6 inhibition beyond progression in the evolving landscape of breast cancer treatment.

This combination offers significant improvement in PFS, especially in patients with longer durations of prior CDK4/6 inhibition and those without visceral metastases and may be a preferred strategy in the second-line setting for patients who have progressed on initial CDK4/6-based therapies, particularly when biomarker-specific therapies are not available.

Abemaciclib plus fulvestrant vs fulvestrant alone for HR+, HER2- advanced breast cancer following progression on a prior CDK4/6 inhibitor plus endocrine therapy: Primary outcome of the phase 3 postMONARCH trial. Kalinsky K, Bianchini G, Hamilton EP, et al. J Clin Oncol 42, 2024 (suppl 17; abstr LBA1001). DOI 10.1200/JCO.2024.42.17_suppl.LBA1001

Late Breaking Abstract – ASCO 2024: Integrating Carboplatin in Early Stage 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 TNBC.

Conventionally, TNBC has been treated with cytotoxic chemotherapy regimens incorporating anthracyclines and taxanes, which remain foundational despite ongoing exploration of novel agents. The role of immune checkpoint inhibitors such as Pembrolizumab (KEYTRUDA®) has expanded into neoadjuvant settings, in addition to its consistent Progression Free Survival (PFS) and Overall Survival (OS) benefits in advanced TNBC. Recent studies have investigated the addition of platinum agents due to their ability to induce DNA damage and apoptosis in tumors with defective DNA repair mechanisms, such as those seen in BRCA-mutated breast cancer. Triple-Negative Breast Cancers that do not harbor BRCA1/2 mutations show defects in the DNA repair mechanism, similar to BRCA1/2 mutant TNBC, and are called BRCAness. Platinum agents have shown promise in increasing the pCR rate when combined with standard taxane and anthracycline regimens in neoadjuvant settings, potentially enhancing outcomes for patients who otherwise face high recurrence risks. The importance of achieving pCR has been underscored by studies like the CTNeoBC pooled analysis, which demonstrated significantly improved survival outcomes in TNBC patients who achieved pCR, compared to those with residual disease. This has prompted the exploration of combination therapies aimed at maximizing response rates and minimizing residual disease burden.

PEARLY is a randomized, multicenter, open-label, Phase III trial in which anthracyclines followed by taxane was compared with anthracyclines followed by taxane plus Carboplatin as (neo)adjuvant therapy in patients with TNBC. Patients with Stage II or III TNBC who need adjuvant or neoadjuvant chemotherapy were included. Any prior systemic therapy for breast cancer was not allowed. In this study, 868 patients (N=868) were randomized 1:1 to either standard arm treatment, which consisted of Doxorubicin 60 mg/m2 IV along with Cyclophosphamide 600 mg/m2 IV every 3 weeks for 4 cycles followed by taxane treatment (Paclitaxel 80 mg/m2 IV weekly for 12 doses or Docetaxel 75mg/m2 IV every 3 weeks for 4 cycles), or experimental group in which Carboplatin AUC5 IV every 3 weeks for 4 cycles was added during taxane treatment. Patients were stratified based on the nodal status (N0 versus N+), treatment setting (neoadjuvant versus adjuvant), and BRCA mutation status (positive versus negative). Patients with bilateral, metastatic, and inflammatory breast cancer were excluded. The Primary objective was to evaluate 5-year Event Free Survival (EFS) rate in the enrolled patients. Secondary objectives included Overall Survival (OS), Distant Recurrence-Free Survival (DRFS), pathologic Complete Response (pCR), and tolerability.

At a median follow up of 51.1 months, Carboplatin significantly improved the 5-year EFS compared to the control arm (HR 0.68; P=0.017). The 5-year EFS rates were increased from 74.4% to 81.9% with the addition of Carboplatin, demonstrating a 7.5% absolute difference in EFS rates. Subgroup analysis showed consistent benefits across various patient subgroups. Secondary endpoints such as OS and DRFS showed favorable trends in the Carboplatin group, although OS data were not mature at the time of reporting. Grade 3 or more treatment-related Adverse Event rates were 74.6% in the Carboplatin group and 56.7% in the control group, but were generally manageable.

In conclusion, the PEARLY trial demonstrated that the addition of Carboplatin to standard anthracycline followed by taxane therapy significantly improved Event-Free Survival in early-stage Triple-Negative Breast Cancer. These findings suggest that Carboplatin has a role in enhancing treatment outcomes in TNBC, particularly by reducing the risk of recurrence. Further research and longer-term follow-up are necessary to fully validate these results and refine treatment strategies for this challenging subtype of breast cancer.

A randomized, multicenter, open-label, phase III trial comparing anthracyclines followed by taxane versus anthracyclines followed by taxane plus carboplatin as (neo) adjuvant therapy in patients with early triple-negative breast cancer: Korean Cancer Study Group BR 15-1 PEARLY trial. Sohn J, Kim GM, Jung KH, et al. Journal of Clinical Oncology. Volume 42, Number 17_suppl. https://doi.org/10.1200/JCO.2024.42.17_suppl.LBA502

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.