Tag: Breast Cancer

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.

Dato-DXd for Patients with HR-Positive HER2-Negative Advanced 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.

Approximately 70% of breast tumors in patients with metastatic disease are Estrogen Receptor (ER) and/or Progesterone Receptor (PR) positive and HER2-negative. 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.

Datopotamab-deruxtecan (Dato-DXd) is an ADC composed of a TROP2-directed monoclonal antibody conjugated to a potent topoisomerase I inhibitor via a stable tetrapeptide-based cleavable linker. Trop-2 is a transmembrane calcium signal transducer that stimulates cancer cell growth. Trop-2 is overexpressed in several epithelial cancers including cancers of the breast, colon and lung, and has limited expression in normal human tissues. It has been associated with poor Overall and Disease-Free Survival in several types of solid tumors. Trop-2 is expressed in more than 85% of breast tumors including Triple Negative Breast Cancer. Upon binding to Trop-2, the anti-TROP-2 monoclonal antibody is internalized and delivers the payload directly into the tumor cell, making it a suitable transporter for the delivery of cytotoxic drugs. Further, the cleavable linker enables the payload to be released both intracellularly into the tumor cells, as well as the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the active drug in bystander cells to which the conjugate has not bound. Dato-DXd showed encouraging antitumor activity in the TROPION-PanTumor01 trial, an ongoing multicenter, open-label study, evaluating Dato-DXd in different dose levels in solid tumors.

TROPION-Breast01 is an open-label, global, Phase III study in which 732 patients (N=732) with HR-positive HER2-negative previously treated metastatic breast cancer were randomly assigned in a 1:1 manner to receive either Dato-DXd (N=365) or investigators choice of chemotherapy (N=367). Dato-DXd was given at a dose of 6 mg/kg IV on day 1 every 3 weeks. Investigators choice of chemotherapy consisted of Eribulin mesylate, Vinorelbine, or Gemcitabine, all given IV on days 1 and 8 every 3 weeks, as well as Capecitabine given orally on days 1-14 every 3 weeks. Treatment was continued until disease progression or unacceptable toxicities. The median age was 55 years and enrolled patients had received 1 or 2 prior lines of chemotherapy in the inoperable or metastatic setting. Eligible patients had progressed on, or were deemed unsuitable for endocrine therapy. Patients were stratified by number of lines of chemotherapy received in the unresectable/metastatic setting, and treatment with a previous CDK4/6 inhibitor. The Co-Primary end points were Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) and Overall Survival (OS). Secondary end points included Overall Response Rate (ORR), Safety, Patient Reported Outcomes, and Time to First Subsequent Therapy (TFST).

The Median PFS by BICR in the Dato-DXd arm was 6.9 months versus 4.9 months in the chemotherapy arm (HR=0.63; P < 0.0001). The PFS rates at 6, 9, and 12-months in Dato-DXd arm were 55.2%, 34.7%, and 21.7%, respectively. In the chemotherapy arm, these rates were 36.9%, 20.9%, and 9.9%, respectively. The PFS benefit with Dato-DXd over chemotherapy was noted irrespective of brain metastases and prior duration of treatment with CDK4/6 inhibitors. The median Time to First Subsequent Therapy was 8.2 months with Dato-DXd and 5.0 months with chemotherapy. Dato-DXd also demonstrated a delay in time to deterioration in global health status/quality of life, compared to chemotherapy.

Treatment-related adverse effects occurred in 94% of patients in the Dato-DXd arm versus 86% in the chemotherapy group, with grade 3 or higher severity in 21% versus 45%, respectively. Neutropenia was more common in the chemotherapy arm.

It was concluded that Dato-DXd showed statistically significant and clinically meaningful improvement in Progression Free Survival compared to chemotherapy. The improved outcomes were observed across subgroups, including patients with and without brain metastases, and those with varying durations of prior CDK4/6 inhibitor treatment. Dato-DXd was associated with a favorable safety profile and impact on quality of life.

Randomized phase 3 study of datopotamab deruxtecan vs chemotherapy for patients with previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer: Results from TROPION-Breast01. Bardia A, Jhaveri K, Im S-A, et al. Presented at San Antonio Breast Cancer Symposium 2023. December 5-9, 2023. San Antonio, TX. Abstract GS02-01.

TUKYSA® Plus KADCYLA® in Advanced HER2-Positive 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 USA, 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 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. HER2-targeted therapies include HERCEPTIN® (Trastuzumab), TYKERB® (Lapatinib), PERJETA® (Pertuzumab), KADCYLA® (ado-Trastuzumab emtansine, T-DM1), ENHERTU® (Trastuzumab deruxtecan) and MARGENZA® (Margetuximab). Dual HER2 blockade with HERCEPTIN® and PERJETA®, given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2-positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival (OS). The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies. Patients progressing on Dual HER2 blockade often receive KADCYLA® which results in an Objective Response Rate (ORR) of 44% and a median PFS of 9.6 months, when administered after HERCEPTIN® and a Taxane.

With advances in systemic therapies for this patient population, the incidence of brain metastases as a sanctuary site has increased. Approximately 50% of patients with HER2-positive metastatic breast cancer develop brain metastases. However, systemic HER2-targeted agents, including Tyrosine Kinase Inhibitors, as well as chemotherapy have limited antitumor activity in the brain. Local therapeutic interventions for brain metastases include neurosurgical resection and Stereotactic or Whole-Brain Radiation Therapy. There is a high unmet need for systemic treatment options to treat established brain metastases and reduce the risk for progression in the Central Nervous System (CNS).

TUKYSA® (Tucatinib) is an oral Tyrosine Kinase Inhibitor that is highly selective for the kinase domain of HER2 with minimal inhibition of Epidermal Growth Factor Receptor. In the HER2CLIMB international, randomized, double-blind, placebo-controlled trial, a combination of TUKYSA® plus HERCEPTIN® and XELODA® (Capecitabine) was compared with placebo plus HERCEPTIN® and XELODA®. TUKYSA® combination significantly improved Progression Free and Overall Survival in heavily pretreated patients, including those with brain metastases.

The HER2CLIMB-02 trial is a randomized, double-blind, placebo-controlled Phase III trial conducted to evaluate the efficacy and safety of the combination of TUKYSA® and KADCYLA® in patients with metastatic HER2-positive breast cancer, particularly those with brain metastases. This study focused on patients with brain metastases, given the limited options for managing breast cancer brain metastases. In this study, 463 patients (N=463) with unresectable locally advanced or metastatic HER2-positive breast cancer were randomly assigned in a 1:1 ratio to receive either 21-day cycles of either TUKYSA® at 300 mg orally twice a day and KADCYLA® 3.6 mg/kg IV every 3 weeks (N=228) or KADCYLA® and placebo (N=235). Both treatment groups were well balanced. The median age was 55 years, eligible patients had been previously treated with HERCEPTIN® and a Taxane in any setting, and trial entry criteria included enrollment of previously treated, stable, progressing, or untreated brain metastases not requiring immediate local therapy. Approximately 40% of all patients had baseline active or stable brain metastasis, and the researchers noted that this was the second large trial, prospectively designed to evaluate systemic therapy in patients with brain metastases. The Primary endpoint was Progression Free Survival (PFS).

At a median follow up was 24.4 months, the combination of TUKYSA® plus KADCYLA® showed a significant improvement in median PFS compared to KADCYLA® alone. The median time to disease progression or death was 9.5 months with TUKYSA® plus KADCYLA® versus 7.4 months with KADCYLA® alone, suggesting a 24% reduction in the risk of disease progression or death with the combination treatment. Among patients with brain metastasis at baseline, the median time to disease progression or death was 7.8 months with the TUKYSA® plus KADCYLA® combination versus 5.7 months with KADCYLA® alone, suggesting a 36% reduction in the risk of disease progression or death with the combination. Further, patients in the TUKYSA® plus KADCYLA® group had a higher Objective Response Rate compared to the control arm (42% versus 36.1%). Overall survival data were immature at the time of this analysis. The combination treatment group reported more treatment related adverse events which included nausea, diarrhea, fatigue and liver function abnormalities.

It was concluded that the combination of TUKYSA® and KADCYLA® demonstrated a statistically significant improvement in Progression Free Survival, compared to KADCYLA® alone, supporting its efficacy in patients with HER2-positive metastatic breast cancer. This study was prospectively designed to evaluate novel systemic therapies in patients with brain metastases, and findings from this study suggested that the combination of TUKYSA® and KADCYLA® could be a favorable treatment option, especially for patients with active or progressing brain metastases. It should be noted that this study did not directly compare the experimental regimen of TUKYSA® and KADCYLA® with other established regimens like TUKYSA® plus HERCEPTIN® and XELODA® or regimens containing ENHERTU®.

HER2CLIMB-02: randomized, double-blind phase 3 trial of tucatinib and trastuzumab emtansine for previously treated HER2-positive metastatic breast cancer. Hurvitz SA, Loi S, O’Shaughnessy J, et al. Presented at the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX. Session GS01-10.

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 300,590 new cases of breast cancer were diagnosed in 2023 and about 43,700 individuals died 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).

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. Published online December 13, 2023. doi:10.1001/jamasurg.2023.6382

Less Frequent Mammography after Curative Treatment in Older Women with 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 approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 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.

Currently, the major national health care organizations in the US have different recommendations for screening mammography which has led to some confusion and emotional counterarguments. These several different recommendations include 1) Annual screening at ages 40 to 84 years 2) Annual screening at ages 45 to 54 years and then biennially at ages 55 to 79 years 3) Biennial screening at ages 50 to 74 years.
Elderly women with a history of breast cancer have a higher risk for a second breast cancer diagnosis. However, appropriate mammographic surveillance methods for this patient group, remains unclear. The widespread practice of annual surveillance mammograms for an unspecified period of time after treatment for early breast cancer can be a significant burden of health care costs in the US.

Mammo-50 trial is a multicenter, randomized Phase III study conducted to assess annual mammography versus less frequent mammography for up to 9 years, in women 50 years or older at the time of their diagnosis with breast cancer. The goal of this study was to determine the optimum frequency and duration of mammographic surveillance. In this study 5,235 women were randomly assigned 1:1 to undergo annual mammograms (N=2618) or less frequent mammograms (N=2617). Less frequent mammography was defined as every 2 years in patients who underwent breast-conservation surgery (N=2099) and every 3 years in patients who had a mastectomy (N=518). Eligible enrolled patients were 50 years of age or older, had undergone curative-intent treatment for invasive or non-invasive breast cancer, and were 3 years post-surgery. Approximately 83% of women were aged 55-75 years, and 87% had invasive disease between the two cohorts. The compliance rates were 83% for the annual mammogram group and 69% for the less frequent mammography group. Approximately 35% of patients missed mammograms due to the COVID-19 pandemic. The Primary study outcomes were Breast Cancer-specific survival and cost effectiveness, whereas Secondary outcomes included Recurrence Free Interval and Overall Survival.

The researchers noted that the efficacy outcomes with regards to breast cancer-specific survival, 5-year recurrence-free interval and OS were similar between the two cohorts of patients. The breast cancer-specific survival at 5 years was 98.1% among patients in the annual mammography cohort and 98.3% among patients in the less frequent mammography cohort. The 5-year Recurrence Free interval rates were 94.1% for the annual mammography group and 94.5% among patients in the less frequent mammography cohort. The 5-year Overall Survival was 94.7% in the annual mammography cohort and 94.5% in the less frequent mammography cohort. Even though compliance in the less frequent mammography group was lower, a sensitivity analysis confirmed this had no effect on the outcomes.

It was concluded from this trial that less frequent mammograms were no worse than undergoing annual mammograms for this group of women,

Mammographic surveillance in early breast cancer patients aged 50 years or over: Results from the Mammo-50 non-inferiority trial of annual versus less frequent mammography. Dunn JA, Donnelly P, Elbeltagi N, et al. Presented at SABCS 2023. December 5-9, 2023. San Antonio, TX. Abstract GS03-02.

Omitting Adjuvant Radiation Therapy in Younger Low Risk Postmenopausal 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 approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 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. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor-positive (HR-positive), HER2-negative breast cancer is the most frequently diagnosed molecular subtype.

Patient undergoing breast conserving surgery, often receive adjuvant breast radiation therapy to reduce the risk of local recurrence. Radiation therapy however is inconvenient, expensive and can be associated with acute and late toxicities. Several previously published trials explored the omission of radiotherapy in low risk patients, following Breast Conservative Surgery. In the CALGB 9343 trial involving women 70 years or older with Stage I, ER-positive breast cancer, treated with Breast Conservative Surgery, locoregional recurrence at 10 years was 10% among those randomly assigned to omission of radiotherapy group and 2% among those assigned to radiotherapy. Similarly, in the PRIME II trial, women 65 years and older with node-negative tumors 3 cm or smaller in size, treated with Breast Conservative Surgery and Endocrine Therapy, had a local recurrence rate of 10% at 10 years when radiation was omitted versus 1% among those assigned to radiotherapy. In the LUMINA trial, women 55 years of age and over with low grade Luminal A breast cancer following Breast Conserving Surgery, Endocrine Therapy and without radiotherapy, had a local recurrence rate of 2.3% at 5 years. These trials provided a new option to elderly patients who wished to avoid radiotherapy

The IDEA (Individualized Decisions for Endocrine therapy Alone) study is a prospective, multicenter cohort trial, initiated at 13 US institutions in 2015. This single-arm study was designed to explore the feasibility of omitting radiotherapy in younger postmenopausal patients with early-stage breast cancer, based on genomic assay, in addition to clinicopathologic risk factors. The IDEA study was inspired by the desire to expand treatment options for de-escalation of therapy for patients with low molecular risk early stage breast cancer, based on prospective clinical data. In this study 200 eligible patients (N=200) were enrolled. This trial included postmenopausal patients 50-69 years of age, with pT1N0 unifocal invasive breast cancer, with margins 2 mm or more after lumpectomy, whose tumors were ER-positive, PR-positive and HER2-negative, with Oncotype DX 21-gene recurrence score of 18 or less. Patients consented to at least 5 years of Endocrine Therapy after lumpectomy and omitting radiotherapy. The mean age was 62 years, mean tumor size was 10 mm and mean 21-gene recurrence score was 11. Histology was ductal in 85% and lobular in 10%, 42.5% had Grade I, 54.5% had Grade II, and 3% had Grade III tumors, respectively, and lymphovascular invasion was present in 14% of tumors. Patients with bilateral disease, a previous personal history of breast cancer, previous radiotherapy to the breast region, or a known carrier of a mutation that predisposes toward breast cancer development (including BRCA-1 and BRCA-2), were excluded. The Primary end point was the rate of locoregional recurrence, 5 years after Breast Conserving Surgery.

With a clinical follow up of at least 56 months among 186 patients, the Overall Survival (OS) and Breast Cancer-Specific Survival rates at 5 years were both 100%. The 5-year freedom from any recurrence was 99%. Crude rates of Ipsilateral Breast Events for the entire follow up period for patients age 50-59 years and age 60-69 years were 3.3% and 3.6%, respectively, and crude rates of overall recurrence were 5.0% and 3.6%, respectively. No distant recurrences were observed.

It was concluded from this study that high disease control can be accomplished at 5 years after omission of radiotherapy, in postmenopausal patients with pT1N0 unifocal invasive breast cancer with favorable biologic features. The authors added that the IDEA study is the first prospective trial to incorporate a genomic assay of low molecular risk, to identify appropriate candidates for omission of breast radiotherapy.

Omission of Radiotherapy After Breast-Conserving Surgery for Women With Breast Cancer With Low Clinical and Genomic Risk: 5-Year Outcomes of IDEA. Jagsi R, Griffith KA, Harris EE, et al. Published online December 07, 2023. DOI: 10.1200/JCO.23.02270 Journal of Clinical Oncology.