Immunotherapy in Triple-Negative Breast Cancer.

ABSTRACT: Triple-negative breast cancer (TNBC) is an aggressive subtype of mammary carcinoma. A subset of TNBC is immune activated, suggesting that immunotherapy may be a viable treatment strategy. Phase III clinical trials have shown that atezolizumab or pembrolizumab is well-tolerated in combination with chemotherapy, with progression-free survival benefit in metastatic programmed death ligand-1 (PD-L1)-positive TNBC patients treated first line. Based on IMpassion130, the combination of atezolizumab and nab-paclitaxel is now considered a standard of care for the treatment of PD-L1-positive advanced TNBC. In early TNBC, pembrolizumab and atezolizumab have been tested in combination with standard neoadjuvant chemotherapy, resulting in a higher complete pathologic response rate than standard neoadjuvant chemotherapy alone, regardless of disease PD-L1 status. These findings establish proof of principle for immunotherapy in both early and advanced TNBC. High priorities for the field include developing more active immunotherapy combination regimens and more refined biomarkers that optimally identify patients most likely to benefit from immunotherapy.

The evolving management of metastatic triple negative breast cancer.

Advanced triple negative breast cancer (TNBC) is an incurable disease classified by its lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2. Due to its lack of therapeutic targets, it has historically been treated with single agent chemotherapy, with combination cytotoxic therapy typically reserved for patients with high disease burdens, symptomatic disease, and/or impending visceral crisis. Recent molecular analyses have revealed that this clinical group of TNBCs is in fact quite biologically heterogeneous, with multiple TNBC subtypes defined by distinct biology and clinical behavior. Building on this biology, 2 targeted strategies are now approved for selected patients with advanced TNBC: the poly (ADP-ribose) polymerase inhibitors for advanced TNBC with a germline mutation in BRCA1/2, and the combination of the programmed death ligand 1-specific antibody atezolizumab with nab-paclitaxel for advanced TNBC that expresses programmed death ligand 1 on immune cells within the tumor. These targeted agents tend to be associated with a more favorable side effect profile and longer disease control than standard chemotherapy. A number of other targeted therapies have shown promise in early clinical trials, and several are now in definitive phase 3 testing for advanced TNBC. These include the antiapoptotic kinase inhibitors ipatisertib and capivasertib, and the antibody-drug conjugate sacituzumab govitecan-hziy. Approved biomarker-driven treatment options for this disease are thus likely to expand in the near-term. Here we review current treatment options and emerging targeted therapies for advanced TNBC. For patients who do not meet criteria for approved targeted therapies, participation in clinical trials evaluating precision medicines with candidate predictive biomarkers in advanced TNBC should be encouraged.

Reflex Estrogen Receptor (ER) and Progesterone Receptor (PR) Analysis of Ductal Carcinoma In Situ (DCIS) in Breast Needle Core Biopsy Specimens: An Unnecessary Exercise That Costs the United States $35 Million/y.

Most institutions reflexively test all breast core needle biopsy specimens showing ductal carcinoma in situ (DCIS) for estrogen receptor (ER) and progesterone receptor (PR). However, 5 factors suggest that this reflex testing unnecessarily increases costs. First, ER/PR results do not currently impact the next step in standard therapy; namely, surgical excision. Second, a subset of surgical excisions performed for DCIS diagnosed on core needle biopsy will harbor infiltrating mammary carcinoma, which will then need to be retested for ER/PR. Third, because ER and PR labeling is often heterogeneous in DCIS, negative results for ER/PR on small core needle biopsy specimens should logically be repeated on surgical excision specimens with larger amounts of DCIS to be sure that the result is truly negative. Fourth, many patients with pure ER/PR-positive DCIS after surgical excision will decline hormone therapy, so any ER/PR testing of their DCIS is unnecessary. Fifth, PR status in DCIS has no proven independent value. We now examine the unnecessary added costs associated with reflex ER/PR testing of DCIS on core needle biopsy specimens due to these factors. We reviewed 58 core needle biopsies showing pure DCIS that also had a resulting surgical excision specimen at our institution over a period of 2 years. No patient received neoadjuvant hormone therapy. On surgical excision, 5 (8.6%) had only benign findings, 44 (75.9%) had pure DCIS, and 9 (15.5%) had DCIS with invasive mammary carcinoma. The 9 cases with invasive mammary carcinoma in the surgical excision specimen (16%) and the 4 pure DCIS in surgical excision specimens that were ER/PR negative on core needle biopsy would need repeat ER/PR testing. The total unnecessary increased cost of core needle biopsy specimen testing of these 13 cases was $8148.92 ($140/patient for the 58 patients in the study). We found that ER/PR testing results impacted patient management in only 16/49 pure DCIS cases after surgical excision (33%), indicating that ER/PR testing costing $20,685.72 ($357/patient in the study) had been performed unnecessarily. PR testing could have been omitted in the 16 cases in which ER/PR results were used, which would have saved $5014.72, or $86.46 per patient. Extrapolating the increased cost of $583 per DCIS diagnosis on core needle biopsy to 60,000 new cases of DCIS in the United States each year, reflex core needle biopsy ER/PR testing unnecessarily increases costs by approximately $35 million. We recommend that ER/PR not be reflexively ordered on core needle biopsy specimens or surgical excision specimens containing DCIS, but instead that ER alone be performed on surgical excision specimens only when hormone therapy is a serious consideration after medical oncology consultation.

Reflex estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2 (ER/PR/Her2) analysis of breast cancers in needle core biopsy specimens dramatically increases health care costs.

ER/PR/Her2 are often reflexively assessed in all core needle biopsies (CNBXs) containing invasive mammary carcinoma (IMC) so that neoadjuvant therapy can be considered. ER/PR/Her2 can be heterogenous, and there is growing consensus that negative results for any of these markers in small CNBXs should be repeated in larger excision specimens (EXS). The frequency and added cost of repeat testing of EXS containing untreated IMC with negative ER/PR/Her2 CNBX results has not previously been studied. We reviewed 198 CNBXs containing IMC, which had reflex ER/PR/Her2 testing and for which there was an EXS for review. We determined the number of cases in which ER/PR/Her2 immunohistochemistry and Her2 fluorescence in situ hybridization were negative on CNBX. Twenty-seven (13.6%) patients received neoadjuvant chemotherapy, and 8 (4%) patients did not have IMC on follow-up EXS, so for them testing the CNBX was necessary. Of the remaining 163 IMCs, 17% were ER negative, and 26% were PR negative, whereas 85% were Her2 negative or equivocal. At our institution, ER/PR were repeated on slightly more than one half of ER/PR-negative tumors, whereas Her2 was repeated on less than one third of Her2-negative/equivocal tumors. Had all negative tests been repeated, the increased cost of testing both the CNBX and EXS would be $100,821. Extrapolating to 230,000 new cases of IMC in the United States each year, the increased cost of repeat testing of all negative ER/PR/Her2 CNBX results would be >$117 million dollars. Limiting reflex testing to ER would decrease the cost of repeat testing to $10 million dollars. We suggest that ER/PR/Her2 should not be reflexively performed on all CNBX specimens containing IMC but instead be routinely performed on EXS and only selectively on CNBX specimens if neoadjuvant chemotherapy is a serious consideration for that individual patient.