The Landmark Series: Neoadjuvant Chemotherapy for Triple-Negative and HER2-Positive Breast Cancer

Abstract

While historically breast cancer has been treated with primary surgery followed by adjuvant therapy, the delivery of systemic therapy in the neoadjuvant setting has become increasingly common, especially for triple-negative and HER2-positive breast cancer. The initial motivations for pursuing neoadjuvant chemotherapy (NAC) were decreasing the tumor burden in the breast and axilla to enable de-escalation of surgery, and use the strategy to advance drug development. While these remain of interest, recent trials have additionally demonstrated survival advantages from escalation of systemic treatment in patients with residual disease, and new studies are testing de-escalation of systemic therapy based on pathologic response. Thus, response information to NAC has become pivotal to guide adjuvant treatment recommendations, and has resulted in NAC being the preferred approach for most HER2-positive and triple-negative breast cancers. Herein, we review select landmark trials that have paved the way for the use of chemotherapy in the neoadjuvant setting for breast cancer.

The central therapies for the management of curable breast cancer are surgical resection, systemic therapy, and radiation therapy. While historically surgery was pursued first followed by adjuvant chemotherapy, the delivery of chemotherapy prior to surgery—neoadjuvant chemotherapy (NAC)—has emerged as the recommended approach in patients with locally advanced disease or aggressive tumor biology. The NAC approach offers multiple advantages as it (1) provides the opportunity to de-escalate surgical management based on response; (2) provides response information that is prognostic and is used to guide adjuvant treatment recommendations; and (3) serves as a platform to advance drug development. This article will review how landmark studies have shaped the current landscape of NAC in breast cancer, especially in triple-negative and HER2-positive subtypes.

From a surgical perspective, downsizing of tumors following NAC may not only render inoperable disease operable but also may convert the surgical plan from mastectomy to breast conservation. Additionally, NAC can eradicate disease from the nodal basin and convert node positive (N +) disease to pathologic node-negative (N −) disease. This has led to de-escalation of axillary surgery by increasing the use of sentinel lymph node surgery and decreasing the use of axillary lymph node dissection, even for those patients who present with clinically N + disease at diagnosis.^1,2

In addition to influencing the extent of surgery, multiple studies have shown that response to NAC impacts prognosis.^3-6 The initial study comparing an adjuvant versus neoadjuvant strategy was the National Surgical Bowel and Breast Project (NSAPB) B-18,⁷ which randomized 1523 women with operable breast cancer to either neoadjuvant or adjuvant doxorubicin (adriamycin) and cyclophosphamide (AC). While overall survival (OS) and disease-free survival (DFS) were similar in the whole population, patients who achieved a pathologic complete response (pCR) after NAC had better DFS and OS than those with residual disease. In this trial, surgeons declared preoperatively if patients were candidates for breast conservation or not, and demonstrated that rates of breast conservation were higher with NAC (68% vs. 60%), especially in larger tumors (cT3). While the pCR rate in this initial study was only 13%, much lower than what is seen currently, this trial was conducted prior to the routine testing for hormone receptors or HER2 to guide systemic therapy selection. Multiple other trials and meta-analyses have shown that NAC is equivalent to adjuvant chemotherapy in terms of survival and disease progression.^8-10 We now know that response rates and breast conservation following NAC are highest in triple-negative and HER2-positive breast cancers,¹¹ the most aggressive subtypes. As such, the use of NAC is highest in these biologic groups.¹²

The findings from NSABP B-18 were corroborated in a pooled analysis³ of 12 international trials including almost 12,000 patients, which demonstrated that those who achieved pCR had improved survival, particularly in triple-negative and hormone receptor-negative, HER2-positive breast cancer treated with trastuzumab. Similarly, 3-year outcome data from the ISPY-2 trial¹³ demonstrate that regardless of breast cancer subtype or treatment regimen, achieving a pCR is associated with an 80% reduction in recurrence rate. Data from 950 patients showed a strong individual-level association between pCR and event-free survival (EFS) and distant recurrence-free survival. While pCR (most commonly defined today as eradication of all invasive disease in the breast and axilla [ypT0/Tis, ypN0]) allows binary prognostication based on response, more granular standardized pathologic response evaluation systems are now used in the clinic. The Residual Cancer Burden (RCB) index categorizes the extent of residual disease in the breast and axilla after NAC into four categories (RCB 0–3).^4,6 A recent meta-analysis of 5160 patients from 12 institutions/clinical trials demonstrated that RCB following NAC can estimate the long-term outcome of patients with all breast cancer subtypes.¹⁴

KEY STUDIES EVALUATING NEOADJUVANT CHEMOTHERAPY (NAC) REGIMENS IN OPERABLE TRIPLE-NEGATIVE BREAST CANCER (TNBC)

Given the accruing evidence demonstrating improved long-term outcomes among patients who achieve a pCR, recent systemic therapy efforts for TNBC have focused on the addition of agents likely to improve pCR rates. In TNBC, the most notable examples are platinums and immunotherapy.

Should Platinums be Routinely Incorporated as Part of NAC Regimens for TNBC?

Genomically, TNBC is characterized by defects in DNA repair mechanisms. Platinums (as well as anthracyclines and cyclophosphamide) directly exert their anticancer effects by inflicting DNA damage, and are highly active in metastatic TNBC, particularly in patients with germline BRCA mutations.¹⁵ Three major studies (Table 1) have demonstrated that the addition of platinum to an NAC regimen leads to higher pCR rates;^16-18 however, enthusiasm for the increased pCR rates is tempered by the additional toxicity (often necessitating dose reductions or cycle eliminations) and by contradictory long-term survival results. While GeparSixto demonstrated an improvement in DFS with carboplatin, the chemotherapy backbone utilized was non-standard. On the other hand, CALGB 40603, which used a more standard backbone including taxanes and two DNA damaging agents (AC), did not demonstrate improvement in EFS or OS with the addition of a platinum. Survival endpoints of the BrighTNess study are awaited to shed further light on this topic.

TABLE 1.

Major studies of carboplatin containing neoadjuvant regimens in triple-negative breast cancer

Study	Chemotherapy backbone	pCR with platinum (%)	pCR without platinum (%)	Toxicity increased?	Completed planned chemotherapy (%)	Survival outcomes improved?
GeparSixto	T + A + Bev	53 p = 0.015	43	Yes	52	Yes
CALGB 40603	T → AC + Bev	54 p = 0.003	41	Yes	64	No
BrighTNess	T ± V → AC	58 p < 0.001	31	Yes	88	NA

pCR pathologic complete response, A anthracycline, Bev bevacizumab, C cyclophosphamide, T taxane, V veliparib

Incorporation of Immunotherapy into NAC Regimens for TNBC

The recent successes of immunotherapy in melanoma, lung, and genitourinary cancers have driven great interest in incorporating it into breast cancer. The interaction between PD-1 (programmed cell death receptor 1) and its ligand PD-L1 (programmed cell death ligand 1) constitutes a key immune checkpoint that negatively regulates T cell activity, and is exploited by tumors to escape immune surveillance. Inhibition of the interaction between PD-1 and PD-L1 has been used successfully in multiple tumors to restore or enhance the endogenous antitumor immune response. Atezolizumab, a PD-L1 inhibitor, and pembrolizumab, a PD-1 inhibitor, are both approved in combination with chemotherapy for patients with untreated metastatic PD-L1-positive TNBC.¹⁹ The three most prominent studies evaluating the addition of immunotherapy to NAC^20-22 are summarized below, and additional studies^23,24 are shown in Table 2.

TABLE 2.

Neoadjuvant immunotherapy studies in triple-negative breast cancer

Study	Chemotherapy backbone	ICI agent	pCR with ICI versus not (ITT)	pCR with ICI versus not (PD- L1-positive)a	pCR with ICI versus not (PD-L1-negative)
I-SPY2	T → AC	Pembrolizumab	60% versus 22%	NA	NA
IMpassion031	Nab-paclitaxel → AC	Atezolizumab	58% versus 41% (p = 0.004)	69% versus 49%	48% versus 34%
KEYNOTE-522	Cb + T → AC	Pembrolizumab	65% versus 51% (p < 0.001)	69% versus 55%	45% versus 30%
GeparNuevo	Nab-paclitaxel → EC	Durvalumab	53% versus 44% (p = 0.287)	58% versus 50%	44% versus 18%
NeoTrip	Cb + Nab-paclitaxel	Atezolizumab	44% versus 41% (p = 0.66)	52% versus 48%	32% versus 32%

A doxorubicin, C cyclophosphamide, Cb carboplatin, E epirubicin, ICI immune checkpoint inhibitor, ITT intention-to-treat, T paclitaxel, pCR pathologic complete response, PD-L1 programmed cell death ligand 1, NA not available

^aPD-L1-positive defined as ≥ 1% expression in immune cells in IMpassion031, ≥ 1% expression in immune cells or tumor cells in GeparNuevo; and as combined positive score ≥ 1% in KEYNOTE-522

I-SPY2²⁰ is an open-label, multicenter, adaptively randomized phase II platform neoadjuvant trial where patients with stage II–III breast cancer receive standard paclitaxel followed by AC versus the same backbone plus investigational agent(s) added. Multiple investigational arms are explored in parallel. The primary endpoint is estimated pCR rate. One of the agents evaluated in I-SPY2 was pembrolizumab, to test whether its addition to standard NAC would likely be successful in a confirmatory randomized phase III trial. The final analysis included 250 women, with 69 randomized to NAC + pembrolizumab, while 181 received NAC alone. Pembrolizumab tripled the estimated pCR rates in TNBC (22% with placebo, 60% with pembrolizumab), and doubled it in the ER-positive/HER2-negative group (13% vs. 30%).

KEYNOTE-522²¹ was designed to determine whether pembrolizumab added to standard NAC improved pCR rates and EFS in patients with operable TNBC. This phase III, randomized, placebo-controlled study randomized 1174 patients with clinical stage II–III (but not N3) disease to receive pembrolizumab or placebo (in a 2:1 ratio) with NAC (carboplatin + paclitaxel followed by AC) and for nine additional postoperative cycles regardless of response. The co-primary endpoints were pCR and EFS in the intent-to-treat (ITT) population. Both pCR and EFS were improved with pembrolizumab (pCR: 64.8% vs. 51.2%; 18-month EFS: 91.3% vs. 85.4%). The PD-L1-positive subgroup had higher overall pCR rates, but a benefit was seen regardless of PD-L1 expression.

IMpassion031²² was a smaller phase III trial with a similar design to KEYNOTE-522, but evaluated atezolizumab as the immunotherapy agent, used a platinum-free backbone (nab-paclitaxel followed by AC), and allowed N3 disease. This study randomized 333 patients in 1:1 ratio to atezolizumab or placebo added to NAC. Postoperatively, treatment was unblinded to inform postoperative management. Patients who received preoperative atezolizumab continued it adjuvantly for 11 cycles, while patients who received preoperative placebo were managed per the discretion of the treating investigator. Like in KEYNOTE-522, the PD-L1-positive subgroup achieved higher pCR overall (68.8% with atezolizumab vs. 49.3% with placebo), but a benefit was seen regardless of PD-L1 expression (pCR in the ITT population: 57.6% with atezolizumab vs. 41.1% with placebo). Survival endpoints are not yet mature.

In the three trials, treatment-related adverse events (AEs) were more frequent in patients receiving immunotherapy. The most common AEs of special interest included infusion reactions (10–17 vs. 7–11%), rash (22–49 vs. 15–49%), and endocrinopathies [hypothyroidism (7–14 vs. 0–3%), hyperthyroidism (3–6 vs. 0%), adrenal insufficiency (0–9 vs. 0–1%)]. The rates of adrenal insufficiency were higher in the I-SPY2 trial (9%) than in KEYNOTE-522 and IMpassion031 (0–1%).

A few open questions regarding the incorporation of immunotherapy remain. (1) What is the optimal chemotherapy backbone, i.e. is carboplatin necessary, and should we use solvent-based paclitaxel or nab-paclitaxel? (2) Is there a benefit in continuing immunotherapy after surgery (as in KEYNOTE-522 and IMpassion031)? (3) How will capecitabine (and novel agents) fit in the adjuvant treatment paradigm of patients who do not achieve pCR? (4) Are the toxicities of immunotherapy as acceptable in the curative-intent setting as they may be in the metastatic setting? Further research to address these questions is necessary.

Can NAC be Further De-Escalated in TNBC?

While most neoadjuvant TNBC clinical trials have focused on treatment escalation to increase pCR, subsets of TNBC with heightened sensitivity to specific agents may achieve good outcomes with less (or no) chemotherapy. A notable example is patients with germline BRCA mutations, whose tumors are uniquely sensitive to inhibitors of the poly (ADP-ribose) polymerases (PARPs). PARPs are a group of enzymes that mediate various cellular functions in response to DNA damage, similar to BRCA1 and 2. Cells that lack functional BRCA1 or 2 proteins already have a compromised DNA damage response and become sensitive to PARP inhibition. Two oral PARP inhibitors are currently US FDA approved for patients with metastatic breast cancer and germline BRCA mutations.^25,26 A small phase II pilot study explored the efficacy of oral neoadjuvant talazoparib as a single agent for 20 patients (10 with TNBC) with germline BRCA mutations and operable breast cancer. Impressively, 10 of 19 (53%) achieved pCR. These remarkable results are being studied in a larger confirmatory phase II trial (NCT03499353).

Tailoring Adjuvant Chemotherapy Based on Response to NAC in TNBC

While delivery of chemotherapy in the neoadjuvant setting had been increasing for TNBC and evaluation of response provided valuable prognostic information, this information did not previously guide further systemic therapy. Regardless of response, no additional systemic therapy was administered postoperatively. The CREATE-X trial²⁷ evaluated whether additional systemic therapy with capecitabine (an oral antimetabolite approved for metastatic breast cancer) for patients with residual disease after NAC might improve outcomes compared with no further chemotherapy. CREATE-X randomized 910 patients with HER2-negative disease treated with standard NAC (containing anthracycline, taxane, or both) and with residual disease to adjuvant capecitabine for six to eight cycles or observation. Adjuvant radiotherapy was delivered if indicated and was allowed before or after randomization. The primary endpoint was DFS. The trial was terminated early as the interim analysis showed improvement in DFS. The full analysis set included 887 patients and showed an improvement in 5-year DFS (from 67.6 to 74.1% with capecitabine) and OS (from 83.6 to 89.2% with capecitabine). While this trial did allow hormone receptor-positive disease, the improvement in DFS was almost entirely driven by improved outcomes seen in the TNBC subset (5-year DFS with capecitabine 69.8%, vs. 56.1% without). As such, in clinical practice, adjuvant capecitabine is typically restricted to TNBC patients with residual disease following standard NAC. In CREATE-X, the main toxicities of capecitabine included hand–foot syndrome (73%), leukopenia (63%), thrombocytopenia (55%), anemia (40%), fatigue (30%), diarrhea (22%), and mucositis (21%).

The data from this trial (further confirmed in a recent meta-analysis²⁸) have been practice-changing, and further support the use of NAC over adjuvant chemotherapy in most patients with TNBC. Response evaluation allows for treatment escalation for patients at highest risk of future breast cancer events (while sparing those with a favorable prognosis), a strategy now shown to improve long-term outcomes and currently being adopted by contemporary TNBC trials. Patients with small tumors and no known nodal involvement at presentation (cT1N0) may benefit less from an NAC approach and may be adequate candidates for upfront surgery. However, since systemic therapy is likely to still be pursued regardless of timing of surgery (particularly for T1b/c TNBC), there would be little disadvantage to delivering this systemic therapy neoadjuvantly. These patients may still derive locoregional benefits (i.e. clearance of clinically occult nodal disease, with potential avoidance of axillary lymph node dissection) and gain prognostic response information to preoperative therapy, simply by altering the sequence of therapy.

KEY STUDIES EVALUATING NAC REGIMENS IN OPERABLE HER2-POSITIVE BREAST CANCER

Consistent with the success of HER2-targeted therapy in the metastatic and adjuvant settings, initial studies of NAC in operable HER2-positive breast cancer demonstrated significant increases in pCR rates with the addition of trastuzumab to chemotherapy.^29-31 Subsequent studies evaluated various combinations of HER2-targeted therapies alone or with cytotoxics, suggesting that the inclusion of cytotoxics was still important, with the highest pCR rates achieved with dual HER2-targeting strategies and chemotherapy.³² As HER2 therapies became incorporated as the standard of care, the need for anthracyclines became questionable, as adjuvant non-anthracycline regimens led to similar long-term outcomes,³³ and neoadjuvant anthra-cycline-based regimens did not improve pCR in the context of dual HER2-targeting. Further efforts have evaluated additional systemic therapy de-escalation strategies for patients with low-risk HER2-positive breast cancer,^34,35 and adjuvant therapy escalation for those with residual disease after NAC.³⁶

Trastuzumab and Pertuzumab in the Neoadjuvant Setting (NeoSphere)

NeoSphere was designed to evaluate the preliminary efficacy of single- or dual-agent HER2 blockade with and without a taxane in the neoadjuvant setting. This open-label, phase II, proof-of-concept multicenter trial investigated four neoadjuvant treatment schemes: (1) trastuzumab and pertuzumab with docetaxel (THP); (2) trastuzumab with docetaxel (TH); (3) pertuzumab with docetaxel (TP); and (4) trastuzumab and pertuzumab without chemotherapy (HP), and included patients with operable (including inflammatory) HER2-positive breast cancer.³² Notably, this study was conducted before the widespread adoption of NAC, and only the investigational component of treatment was administered before surgery. Following surgery, all patients received adjuvant anthracycline and cyclophosphamide (as well as fluorouracil), while group 4 also received adjuvant docetaxel. NAC plus dual HER2-blockade (THP) achieved the highest pCR rate: THP 39%, TH 22%, TP 18%, HP 11%. In all treatment arms, pCR rates were higher for hormone receptor-negative tumors. This study provided initial support for the use of dual HER2 blockade with HP plus chemotherapy in patients with operable HER2-positive breast cancer, and further support for the value of NAC in evaluating new drug regimens. It is important to note that today, when NAC is used, all of the chemotherapy is administered prior to surgery, unlike these earlier studies, where part of the chemotherapy (often the investigational component) was administered prior to surgery and the remainder was often administered postoperatively (sandwich therapy).

Key Studies Evaluating Whether Anthracyclines Offer Benefit in HER2-Positive Breast Cancer

Anthracycline and taxane-based regimens are the standard chemotherapy backbone for operable breast cancer; however, controversy has existed over the relative contribution of anthracyclines in the era of effective HER2-targeted therapies. Toxicities (particularly cardiac and risk for secondary leukemias) have driven great interest in eliminating anthracyclines for curable HER2-positive breast cancer. Two major studies addressing this question are the Breast Cancer International Research Group BCIRG-006³³ and TRAIN-2.^34,35 BCIRG-006 studied adjuvant chemotherapy regimens with and without trastuzumab. The study demonstrated that the trastuzumab-containing arms were superior to AC-T, and showed a minimal numerical (but not statistically significant) advantage of AC-TH over TCH (even for node positive patients); however, AC-TH was associated with a fivefold increase in clinically significant heart failure (2% with AC-TH vs. 0.4% with TCH) and a higher rate of treatment-related leukemias (seven cases with AC-TH, none with TCH).

Other non-comparative neoadjuvant studies have suggested that anthracycline-containing regimens plus dual HER2-blockade lead to higher pCR rates,³⁷ adding to the debate. To address this question, the TRAIN-2 study directly compared the efficacy and safety of an anthracycline-containing regimen (fluorouracil, epirubicin, and cyclophosphamide [FEC] followed by paclitaxel + HP) versus an anthracycline-free regimen of paclitaxel and carboplatin + HP. In this study, the inclusion of anthracyclines did not improve pCR rates,³⁴ EFS, or OS, but did increase cardiac toxicity and chemotherapy-associated leukemia,³⁵ corroborating the observations from BCIRG-006. TRAIN-2 supports the notion that in 2020, anthracyclines should not be standard treatment for the majority of operable HER2-positive breast cancers.

Tailoring Adjuvant Chemotherapy Based on Response to NAC in HER2-Positive Breast Cancer

Analogous to the CREATE-X strategy for patients with residual TNBC after NAC, the KATHERINE trial³⁶ evaluated whether adjuvant treatment escalation improved outcomes in patients with residual HER2-positive breast cancer after NAC. KATHERINE enrolled 1486 patients with HER2-positive breast cancer who did not achieve pCR after neoadjuvant taxane-based chemotherapy (with or without anthracycline) and trastuzumab, and randomized them to receive adjuvant trastuzumab emtansine (T-DM1) or standard trastuzumab for 14 cycles. T-DM1 is an antibody–drug conjugate consisting of trastuzumab and the microtubule inhibitor emtansine (DM1), approved for the treatment of metastatic HER2-positive breast cancer that has progressed after trastuzumab and a taxane. The primary endpoint was invasive DFS, and was significantly improved in patients who received T-DM1 (3-year invasive DFS was 88.3% vs. 77.0). The first invasive-disease event was distant recurrence in 10.5% of the T-DM1 group and 15.9% of the trastuzumab group.

Like CREATE-X, the KATHERINE trial has changed practice. Patients who achieve pCR after NAC typically continue trastuzumab after surgery, whereas patients with residual invasive disease switch to T-DM1. This individualization of management based on response to NAC represents a key strategy for improving outcomes for breast cancer patients and underscores the value of delivering therapy neoadjuvantly to these patients.

Can NAC be Further De-Escalated in HER2-Positive Breast Cancer?

Evidence supporting a de-intensified systemic therapy regimen in low-risk small HER2-positive breast cancer comes from the APT trial,³⁸ which showed excellent 3- and 7-year DFS rates of 98.5% and 93.3%, respectively. This study used an adjuvant regimen consisting of paclitaxel and trastuzumab (TH) for patients with pathologically node-negative tumors measuring up to 3 cm, offering the opportunity to use only one cytotoxic drug.³⁹ Given this, upfront surgery with pathological staging of the axilla would allow for the potential of systemic therapy de-escalation from standard taxane, platinum, trastuzumab, and pertuzumab (TCHP) to a much better tolerated regimen of paclitaxel and trastuzumab. This would represent the current standard of care for most patients with stage I HER2-positive breast cancer. However, in an era where response to NAC is used to personalize therapy, further work to optimize NAC regimens according to initial disease presentation features is needed. Could the NAC regimen be safely de-escalated upfront for these patients, with further adjuvant therapy decisions made based on response to a de-escalated regimen? De-escalation of NAC in HER2-positive breast cancer is being evaluated in the CompassHER2 trials (COMprehensive use of Pathologic response ASSessment to optimize therapy in HER2-positive breast cancer). CompassHER2 EA1181 (NCT04266249) is evaluating whether patients with stage II–IIIA HER2-positive disease who achieve pCR following a de-escalated NAC regimen of taxane, trastuzumab, and pertuzumab (THP, without carboplatin) can safely avoid further chemotherapy. Patients with residual disease have the option of receiving additional standard-of-care chemotherapy adjuvantly, or participating in other studies evaluating novel adjuvant regimens. If successful, future studies may evaluate a de-escalated neoadjuvant strategy for patients with low-risk HER2-positive breast cancer, avoiding overtreatment while preserving the potential benefits of locoregional therapy de-escalation.

TAILORING LOCOREGIONAL THERAPY BASED ON RESPONSE TO NAC

One of the most pragmatic potential benefits of NAC versus adjuvant chemotherapy is the de-escalation of surgical treatment. Multiple prior reports support NAC to decrease breast tumor size to facilitate breast conservation when desired. Rates of breast conservation and pCR are highest in patients with TNBC or HER2-positive disease.¹¹ Additionally, a distinct increase is being seen in the use of sentinel lymph node surgery, with or without¹ specific localization of the initial biopsy-proven positive node in patients with clinically node-positive disease, with patient selection guided by post-NAC preoperative imaging.^40,41 This benefit (downstaging axillary disease) is also seen among cN0 patients treated with NAC.⁴² Technical standards for breast oncologic surgery, including those specifically addressing operation after NAC, have been established and published^2,43 and are a focus of ongoing efforts of the newly created Cancer Surgical Standards Program of the American College of Surgeons. A recent ASO Landmark series reviewed the landmark trials in axillary management.⁴⁴

Studies testing whether exceptional responders to NAC might avoid surgery altogether are underway. Institutional studies evaluating image-guided percutaneous biopsy of the tumor bed after NAC showed promising results;^45-49 however, the NRG BR005⁵⁰ showed a disappointing lack of sensitivity (50%) for post-NAC preoperative percutaneous needle biopsy of the tumor bed in identifying persistent residual disease. Extent of evaluation of the tumor bed is a critical factor for this approach. A recent pooled analysis of individual data reported an overall false negative rate of 18.7% across the whole cohort, but also demonstrated that using a standardized protocol with image-guided vacuum-assisted biopsy of tumor beds 2 cm or smaller with six or more samples had a false negative rate of 3.2%.⁵¹ Further improvements in protocols and imaging might lead to this approach taking hold in the future. Other studies are also testing de-escalation of radiation therapy, an approach particularly attractive for patients with HER2-positive disease who have a pCR in the breast and regional nodes.⁵²

Inflammatory Breast Cancer

While patients with locally advanced breast cancer who are treated with NAC can have an excellent response, and benefit from tailoring their surgical mangagement of the breast and the axilla based on response, the standard recommendation for patients with inflammatory breast cancer is modified radical mastectomy (i.e. total mastectomy and axillary dissection without reconstruction), following NAC and preceding comprehensive regional nodal radiation regardless of response to therapy. However, recent reports evaluating contemporary patient cohorts have shown substantial pCR rates in the breast and axillary nodes,^53,54 suggesting that re-evaluation and consideration of surgical de-escalation may be warranted in future clinical trials.

CONCLUSIONS AND FUTURE DIRECTIONS

Data from a multitude of trials have sculpted the current landscape of NAC. NAC has an important role for patients who are known to be candidates for systemic therapy at the time of diagnosis, particularly those with HER2-positive or triple-negative breast cancer. Advances in systemic therapy have resulted in improved pCR rates, a metric that correlates with long-term outcomes and guides recommendations for additional adjuvant therapy. As a result the FDA has adopted pCR as a surrogate marker for new drug approvals in breast cancer.^27,36 Administration of NAC improves the suitability for breast conservation and sentinel lymph node surgery for patients with clinical response. Involvement and discussion with a breast multi-disciplinary team including a medical oncologist, surgical oncologist, and radiation oncologist pior to the initiation of treatment is crucial for the consideration of sequencing of therapy, its impact on all treatment modalities, and ensuring appropriate clip placement in breast lesions and axillary node (in the setting of node-positive disease) to allow de-escalation based on response. The next frontiers in personalizing therapy for patients with breast cancer include the identification of patients with exceptional response to NAC who may be candidates for elimination of surgery altogether; pretherapy identification of patients more likely to achieve pCR to pave the way for studies tailoring neoadjuvant regimens according to promising predictive biomarkers (e.g. tumor-infiltrating lymphocytes,⁵⁵ tumor PD-L1 expression,^21,55 germline BRCA status,⁵⁶ and peripheral blood immune profiles^57,58); and detection of minimal residual disease after completion of NAC (e.g. circulating tumor cells and circulating tumor DNA) to further refine recurrence risk prognostication among patients who do not achieve pCR.⁵⁹