Tag: Breast Cancer

SUMMARY: The Council for Responsible Nutrition reported that 77% of Americans consume dietary supplements. With the growing awareness regarding health, fitness and nutrition, the market size for dietary supplements is projected to hit a valuation of $349.4 billion by 2026.

Patients often use dietary supplements following a diagnosis of cancer, even though clinical recommendations discourage the use of antioxidant supplements during chemotherapy. One of the mechanisms of action of cytotoxic chemotherapeutic agents is through the generation of Reactive Oxygen Species (ROS). The use of dietary supplements during treatment, particularly antioxidants, could reduce the efficacy of cytotoxic agents. DELCaP study was conducted to address this concern.

DELCaP (Diet, Exercise, Lifestyle and Cancer Prognosis) trial is a prospective observational study, ancillary to an intergroup therapeutic clinical trial for high-risk breast cancer, conducted to evaluate associations between supplement use, particularly antioxidants during chemotherapy treatment, and breast cancer survival outcomes.

The Phase III SWOG S0221 trial evaluated the optimal dose and schedule of Anthracycline/Taxane adjuvant chemotherapy in women with high-risk early breast cancer. The current analysis involved a cohort of 1,134 of 2,014 patients enrolled in this study, who answered a baseline and follow-up questionnaires that included their use of dietary supplement at enrollment and during treatment. The authors then analyzed associations of dietary supplement use with clinical outcomes, after adjusting for clinical and lifestyle factors. Approximately 18% of patients used antioxidants such as Vitamins C, A, and E, Carotenoids or Coenzyme Q10 during treatment, whereas 44% of patients took multivitamins during chemotherapy.

It was noted from this analysis that the use of any antioxidant supplement (Vitamins A, C, and E, Carotenoids and Coenzyme Q10), both before and during adjuvant treatment was associated with an increased risk of recurrence versus no such use of supplements (HR=1.41; P=0.06). There was also a nonsignificant increased risk of overall mortality with the use of any antioxidant supplement (HR=1.40; P=0.14). There was a weaker relationship of outcomes with individual antioxidants and this may perhaps be due to the small numbers of patients. With regards to nonoxidants, Vitamin B12 use both before and during chemotherapy was significantly associated with poorer Disease Free Survival (HR=1.83; P<0.01) and Overall Survival (HR= 2.04; P<0.01). Use of iron during chemotherapy was also significantly associated with recurrence (HR=1.79; P<0.01), as was use both before and during treatment (HR=1.91; P=0.06). Results were similar for Overall Survival. Multivitamin use however was not associated with survival outcomes.

The researchers based on this analysis concluded that the use of antioxidant and nonantioxidant dietary supplements, but not multivitamins, before and during adjuvant chemotherapy may be associated with inferior treatment outcomes, in patients with early stage high risk breast cancer. They added that caution should be exercised by patients, when considering the use of supplements, other than a multivitamin, during chemotherapy, and patients should try to get their vitamins and minerals including antioxidants through food products..

Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221). Ambrosone CB, Zirpoli GR, Hutson AD, et al. J Clin Oncol. 2019;38:804-814

SUMMARY: The FDA on April 22, 2020, granted accelerated approval to TRODELVY® (Sacituzumab govitecan-hziy), for adult patients with metastatic Triple-Negative Breast Cancer (TNBC), who received at least two prior therapies for metastatic disease. Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer will be diagnosed in 2020 and about 42,170 women will die of the disease.

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 and African American females. 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 and often develop visceral metastases. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival 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. The lack of known recurrent oncogenic drivers in patients with metastatic TNBC, presents a major therapeutic challenge. Overall survival among patients with pretreated metastatic TNBC has not changed over the past 2 decades and standard chemotherapy is associated with low response rates of 10-15% and a Progression Free Survival of only 2-3 months.

TRODELVY® is an Antibody-Drug Conjugate (ADC) in which SN-38, an active metabolite of Irinotecan, a Topoisomerase I inhibitor, is coupled to the humanized Anti-Trophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody (hRS7 IgG1κ), through the cleavable CL2A linker. SN-38 cannot be given directly to patients because of its toxicity and poor solubility. Trop-2, a transmembrane calcium signal transducer, stimulates cancer-cell growth, and this cell surface receptor is overexpressed in several epithelial cancers including cancers of the breast, colon and lung, and has limited expression in normal human tissues. 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 SN-38 directly into the tumor cell, making it a suitable transporter for the delivery of cytotoxic drugs. Further, the cleavable linker enables SN-38 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. Thus, TRODELVY®-bound tumor cells are killed by intracellular uptake of SN-38, whereas the adjacent tumor cells are killed by the extracellular release of SN-38.

IMMU-132-01 is a Phase I/II, basket design, open-label, single-group, multicenter trial involving patients with various types of advanced epithelial cancers, who have received at least one previous therapy for metastatic disease. (One example of a basket design is a single drug evaluated in multiple baskets, with each basket representing a different malignancy or tumor site with the same target). A total of 108 patients with metastatic Triple-Negative Breast Cancer (TNBC) were enrolled between June 2013 and February 2017. Patients received TRODELVY® 10 mg/kg IV on days 1 and 8 every 21 days. Tumor imaging was obtained every 8 weeks, and patients were treated until disease progression or intolerance to therapy. The median patient age was 55 years. Enrolled patients had a median of 3 prior anticancer regimens and 98% had received taxanes and 86% had received anthracyclines. The Primary efficacy end point was the Objective Response Rate (ORR). Other efficacy end points included Time to Response and Duration of Response in patients who had a response, the Clinical Benefit Rate (defined as a Complete or Partial Response or stable disease for at least 6 months), Progression Free and Overall Survival. The median duration of follow up for this basket of 108 patients with metastatic TNBC was 9.7 months.

The Objective Response Rate was 33.3% including a Complete Response Rate of 2.8%. The median Time to Response was 2.0 months and the median Duration of Response was 7.7 months. The Clinical Benefit Rate was 45.4%. There was no meaningful difference in response rates in the various patient subgroups including patient age, onset of metastatic disease, number of previous therapies and the presence or absence of visceral metastases. The median PFS was 5.5 months and median OS was 13.0 months. The most common adverse reactions were, possibly severe neutropenia and diarrhea, fatigue, nausea, vomiting, alopecia and abdominal discomfort.

It was concluded that TRODELVY® was associated with durable Objective Responses in patients with heavily pretreated metastatic Triple Negative Breast Cancer. This unique Antibody Drug Conjugate may be of potential benefit for other Trop-2 expressing advanced epithelial solid tumors.
Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer. Bardia A, Mayer IA, Vahdat LT, et al. N Engl J Med. 2019;380:741-751.

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer will be diagnosed in 2020 and about 42,170 women will die of the disease. 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) and KADCYLA® (ado-Trastuzumab emtansine). 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. There is however no standard treatment option for this patient population following progression on KADCYLA®.
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®, 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, minimizing systemic exposure. In a Phase 1 dose-finding study involving patients with advanced HER2-positive breast cancer, treatment with ENHERTU® resulted in a confirmed response rate was 59.5%, and the median response duration was 20.7 months. However, the efficacy of ENHERTU® in patients with HER2-positive metastatic breast cancer, previously treated with KADCYLA® remained unclear.
DESTINY-Breast 01 study is a multicenter, single-arm, Phase II registration trial, in which 184 patients with HER2-positive, metastatic breast cancer, who had received two or more prior HER2 targeted therapies including KADCYLA®, were enrolled. Patients received ENHERTU® 5.4 mg/kg IV every 3 weeks until disease progression or unacceptable toxicity. The median age was 55 years, 53% had Hormone Receptor-positive tumors and the median number of previous lines of therapy for metastatic disease was SIX and included KADCYLA® (100%), Trastuzumab (100%), Pertuzumab (66%), and other anti-HER2 therapies (54%). The Primary end point was Objective Response Rate (ORR) assessed by Independent Central Review and Secondary endpoints included Duration of Response, Progression Free Survival (PFS) and Overall Survival (OS). The median follow up was 11.1 months.
The ORR was 60.9%, with 6% Complete Responses and 54.9% Partial Responses. The median time to response was 1.6 months and the median response duration was 14.8 months. The median PFS was 16.4 months the median OS was not reached at the time of this publication. The efficacy results were consistent across all key subgroups, including patients who had received previous PERJETA® (Pertuzumab) therapy. The most Grade 3 or higher adverse events were cytopenias, nausea, diarrhea and Interstitial Lung Disease.
It was concluded that ENHERTU® has a high level of clinical efficacy with a durable antitumor activity in a heavily pretreated patient population with HER2-positive metastatic breast cancer. The FDA in December 2019, granted accelerated approval to ENHERTU® (Trastuzumab deruxtecan) for patients with unresectable or metastatic HER2-positive breast cancer, who have received two or more prior anti-HER2-based regimens in the metastatic setting. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. Modi S, Saura C, Yamashita T, et al. for the DESTINY-Breast01 Investigators. N Engl J Med 2020;382:610-621.

SUMMARY: The FDA on February 25, 2020, approved NERLYNX® (Neratinib) in combination with XELODA® (Capecitabine) for adult patients with advanced or metastatic HER2-positive breast cancer, who have received two or more prior anti-HER2 based regimens in the metastatic setting. Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer will be diagnosed in 2020 and about 42,170 women will die of the disease. 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.
NERLYNX® (Neratinib) is a potent, irreversible, oral Tyrosine Kinase Inhibitor, of HER1, HER2 and HER4 (pan-HER inhibitor). NERLYNX® interacts with the catalytic domain of HER1, HER2, and HER4 and blocks their downstream signaling pathways, resulting in decreased cell proliferation and increased cell death. Clinical data has suggested that NERLYNX® has significant activity in suppressing HER-mediated tumor growth and is able to overcome tumor escape mechanisms experienced with current HER2-targeted and chemotherapeutic agents. It has been well known that hormone receptor positive breast cancer patients, who are also HER2-positive, have relative resistance to hormone therapy. Preclinical models had suggested that the addition of NERLYNX® could improve responses in ER positive, HER2-positive breast cancer patients. Further, NERLYNX® has clinical activity in patients with HER2-positive metastatic breast cancer. NERLYNX® is the first TKI approved by the FDA, shown to reduce the risk for disease recurrence, in patients with early stage HER2-positive breast cancer. NERLYNX® when given for 12 months after chemotherapy and HERCEPTIN®-based adjuvant therapy, to women with HER2-positive breast cancer, significantly reduced the proportion of clinically relevant breast cancer relapses that might lead to death, such as distant and locoregional recurrences outside the preserved breast.
TYKERB® (Lapatinib) is a Tyrosine Kinase Inhibitor of HER2 and EGFR, and in a previously published Phase III study, a combination of TYKERB® plus XELODA® (Capecitabine) was found to be superior to XELODA® alone in women with HER2-positive advanced breast cancer, that has progressed after treatment with regimens that included an Anthracycline, a Taxane, and HERCEPTIN®. (N Engl J Med 2006; 355:2733-2743)
NALA is a multinational, randomized, open-label, Phase III trial of NERLYNX® plus XELODA® in patients with heavily pretreated Stage IV HER2-positive metastatic breast cancer. In this study, 621 patients with metastatic HER2-positive breast cancer who received two or more prior anti-HER2 based regimens in the metastatic setting were randomly assigned in a 1:1 to receive NERLYNX® 240 mg given orally once daily on days 1-21 along with XELODA® 750 mg/m2 given orally twice daily on days 1-14 for each 21-day cycle (N=307) or TYKERB® 1250 mg given orally once daily on days 1-21 along with XELODA® 1000 mg/m2 given orally twice daily on days 1-14 for each 21-day cycle (N=314). Approximately 80% had visceral metastases, and about 30% had received at least three anti-HER2 therapies. Patients in the NERLYNX® group also received antidiarrheal prophylaxis with Loperamide. Patients were treated until disease progression or unacceptable toxicity. The Co-Primary endpoints were Progression Free Survival (PFS) and Overall Survival (OS). Secondary endpoints included Objective Response Rate (ORR) and Duration of Response, Clinical Benefit Rate (CBR), time to intervention for symptomatic metastatic Central Nervous System (CNS) disease and Safety.
It was noted that the median PFS was 5.6 months for patients who received NERLYNX® with XELODA® and 5.5 months for those receiving TYKERB® with XELODA® (HR=0.76; P=0.006). This represented a 24% reduction in the risk of disease progression or death for those receiving a combination of NERLYNX® and XELODA®. The PFS rate at 12 months was 29% versus 15% respectively. The median OS was 21 months for patients receiving NERLYNX® and XELODA® compared to 18.7 months for those receiving TYKERB® and XELODA® (HR=0.88; P=0.20). The ORR was numerically higher with NERLYNX® and XELODA® combination in patients with measurable disease (32.8% versus 26.7%), and there was a statistically significant improvement in the Clinical Benefit Rate (45% versus 36%; P=0.03). The median Duration of Response was 8.5 versus 5.6 months respectively (HR=0.50; P=0.0004), favoring the NERLYNX® combination. The time to intervention for symptomatic CNS disease was significantly delayed with NERLYNX® combination versus TYKERB® combination, with an overall cumulative incidence of 22.8% versus 29.2% respectively (P= 0.043). Treatment related toxicities were similar between arms, but there was a higher rate of Grade 3 diarrhea with the NERLYNX® combination (24.4% versus 12.5% respectively). Discontinuation due to treatment related toxicities were lower with NERLYNX® combination versus TYKERB® combination (10.9% versus 14.5%).
It was concluded from this study that a combination of NERLYNX® and XELODA® significantly improved Progression Free Survival, with a trend towards improved Overall Survival, and also resulted in a delayed time to intervention for symptomatic CNS disease, among patients with heavily pretreated advanced HER2-positive breast cancer. Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial. Saura C, Oliveira M, Feng Y-H, et al. J Clin Oncol. 2019;37 (suppl; abstr 1002).

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. Approximately 279,100 new cases of invasive breast cancer will be diagnosed in 2020 and about 42,690 individuals will die of the disease. Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. 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. The understanding of the role of Cyclin Dependent Kinases in the cell cycle, has paved the way for the development of CDK inhibitors.
KISQALI® (Ribociclib) is an orally bioavailable, selective, small-molecule inhibitor of CDK4/6, that blocks the phosphorylation of RetinoBlastoma protein, thereby preventing cell-cycle progression and inducing G1 phase arrest. KISQALI® in combination with an Aromatase Inhibitor has been approved by the FDA for pre and perimenopausal women with HR (Hormone Receptor)-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine-based therapy. The efficacy of KISQALI® was evaluated in two prior randomized Phase III studies. In the MONALEESA-2 trial which evaluated KISQALI® in combination with FEMARA® (Letrozole) compared to FEMARA® alone, in postmenopausal women with HR-positive, HER2-negative advanced breast cancer, who received no prior therapy for their advanced breast cancer, the addition of KISQALI® to FEMARA® significantly prolonged Progression Free Survival (PFS) compared to FEMARA® alone. In the MONALEESA-7 study, KISQALI® in combination with Tamoxifen or a Non-Steroidal Aromatase Inhibitor plus ZOLADEX® (Goserelin) was compared with Tamoxifen or an Aromatase Inhibitor plus ZOLADEX®, in premenopausal or perimenopausal women with HR-positive, HER2- negative advanced breast cancer, who had not previously received endocrine therapy for advanced disease. In this study of premenopausal women, KISQALI® plus endocrine therapy significantly improved PFS and OS, compared with placebo plus endocrine therapy.
MONALEESA-3 is a randomized, double-blind, placebo-controlled Phase III study which compared the efficacy of KISQALI® in combination with FASLODEX® with FASLODEX® alone, among postmenopausal women with HR-positive, HER2-negative advanced breast cancer, who received no prior or only one line of prior endocrine therapy for advanced disease. In this trial, 726 women were randomized, of whom 367 were treatment-naïve and 345 patients had received up to one line of prior endocrine therapy for advanced disease. . Patients were randomized 2:1 to receive KISQALI® plus FASLODEX® (N=484) or placebo plus FASLODEX® (N=242). Treatment consisted of KISQALI® 600 mg orally daily 3 weeks on and 1 week off and FASLODEX® 500 mg IM on day 1 of each 28-day cycle, with an additional dose given on day 15 of cycle 1. Patients were stratified by the presence or absence of lung or liver metastases and prior endocrine therapy (first-line versus second-line). The median age in both groups was 63 years. The Primary endpoint was Progression Free Survival (PFS). Secondary end points included Overall Survival (OS), Overall Response Rate (ORR), and Safety.
In the primary analysis of the trial, the median PFS in the KISQALI® plus FASLODEX® group was 20.5 months compared to 12.8 months in the FASLODEX® plus placebo group (HR= 0.59; P<0.001). This represented a 41% reduction in the risk of disease progression. The authors now report the results of the second interim analysis of Overall Survival and an updated analysis of Progression Free Survival. The median duration of follow up for all patients was 39.4 months, and the median duration of treatment was 15.8 months in the KISQALI® group and 12.0 months in the placebo group.
There was a significant Overall Survival benefit with KISQALI® plus FASLODEX® compared to placebo plus FASLODEX®. The estimated Overall Survival at 42 months was 57.8% in the KISQALI® group compared to 45.9% in the placebo group, and this represented a 28% reduction in the relative risk of death with the KISQALI® combination (HR=0.72; P=0.00455). The survival benefit was consistent across most subgroups. The median PFS among patients receiving first line treatment was 33.6 months (95% CI, 27.1 to 41.3) in the KISQALI® group and 19.2 months in the placebo group. No new safety signals were observed during this longer follow up period.
It was concluded that KISQALI® plus FASLODEX® significantly improved Overall Survival compared to placebo plus FASLODEX® in patients with HR-positive, HER2-negative advanced breast cancer, regardless of whether they received their treatment in the frontline setting or subsequently. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. Slamon DJ, Neven P, Chia S, et al. N Engl J Med 2020;382:514-524