Abstract

The indications for postoperative radiotherapy after surgery following neoadjuvant systemic therapy for breast cancer are reviewed and the controversial issues summarized. Current standards and areas of future development are delineated. The need of collecting data on radiotherapy characteristics and results, according to different clinical and biological parameters, in the framework of perspective clinical studies, is underlined.

Background and Radiotherapy-Related Issues

Neoadjuvant systemic therapy (NAST) of breast cancer can obtain locoregional control and survival rates no worse than those achieved with postsurgical adjuvant chemotherapy. A previous meta-analysis of the trials comparing NAST with adjuvant chemotherapy casted some doubts on the equivalence of the two strategies in terms of locoregional control, especially in some subgroups of patients (1); however, the updated results of this study and recent retrospective analyses do not seem to justify these worries (2,3). The upfront use of systemic therapy does not provide a superior alternative to the “standard” therapeutic sequence in terms of survival; however, it is safe and can (at least in theory) offer other advantages. Schematically, they can be synthesized as follows:

  • Reduction of tumor burden

  • In vivo monitoring of response to systemic agents

  • Higher rates of breast conserving surgery (BCS)

  • Collection of useful prognostic information

  • “Tailored” treatment decisions

The adoption of NAST implies also that a fundamental component of the integrated treatment of breast cancer, namely, radiotherapy (RT) should be given in a different clinical context. A few key points, raising RT issues, and therefore to be addressed to optimize radiation treatment, are linked with the extent of surgery, “old” and “new” predictors of local and distant failure and future efforts to better tailor treatment to the individual patient.

Extent of Surgery, “Old” and “New” Predictors of Local and Distant Failure

NAST is usually reserved to high-risk breast cancer patients, since the rationale for its use relies in part on the need of early treatment of micrometastases in patients for whom they represent a major risk. Therefore, the published evidence refers mainly to locally advanced cases (inflammatory cancer, T3 or “large volume” T2 cases). The possible indications to NAST include also cases with unfavorable biological features (“triple negative,” high grade histology, HER2 positivity, high proliferation index in oestrogen receptor-positive tumors) (2). It is not surprising, therefore, that the majority of patients given NAST is subsequently submitted to a mastectomy. For example, in the NAST series reported by Delpech et al. (4), including only oestrogen receptor-positive patients, about two-thirds of the 1718 cases with infiltrating ductal carcinomas had a mastectomy, even if almost 70% of them had T1-2 tumors; the mastectomy rate rises to about 80% for invasive lobular carcinomas.

The scenario for the radiation oncologist facing the question of the indication to RT and of RT options after NAST is obviously different for the minority of cases treated with BCS and for those who had a mastectomy.

After BCS, RT options are similar to those adopted for the cases not submitted to NAST, but some differences should be underlined. Whole breast treatments are indicated, since it could be well hypothesized that “small foci of residual tumor might not be visualized on imaging studies and could be missed with a standard lumpectomy margin assessment” (5). The indications for NAST in the case of invasive lobular carcinomas are weak, and whole breast RT is even more needed in patients with this histological subtype, due to its unique anatomical features, that make the intraoperative margins determination less easy (4). A boost to the tumor bed is indicated, as for the cases not having NAST. Boost volume determination is less easy, however, since the initial tumor volume may only be derived from the imaging studies done at presentation. In conclusion, the possibility of omitting RT in selected cases after BCS, the use of intraoperative radiation, of different fractionation schemes and treated volumes (eg, accelerated partial breast irradiation, hypofractionation) remains to be investigated and cannot be considered a standard (2).

After NAST and mastectomy, the indications for postoperative RT are more questionable. In cases not given NAST, mastectomy is mostly reserved to large volume, prognostically unfavorable cases. Postoperative RT in this setting has been shown to reduce the risk of locoregional recurrence and to improve survival (6). The need for postoperative RT is usually defined according to the pathologist’s report. A growing consensus identifies a number of axillary involved nodes greater than three, positive resection margins, T3-T4 categories as strong indications to postoperative RT.

When NAST is given, the initial pathological extent of the disease in the breast and in the nodes is often masked by the effects of systemic therapy. However, a dated but very useful report on the large MD Anderson Cancer Center experience with more than 700 patients treated 1974–2000 with adriamycin-based NAST concluded that the use of postmastectomy RT confers a locoregional control and survival advantage to patients with clinical T3-4 tumors, supraclavicular nodes involvement and with four or more involved axillary nodes (7). This represents a valuable effort to build on “classic” predictors of relapse/survival in a new clinical scenario, but leaves many questions unanswered.

Recently, the five cancer centers of the University of California produced a detailed critical review of the existing literature on the subject, due to the lack of randomized studies (8). The Delphi technique was used to identify clinical case scenarios and to decide on the appropriateness of postmastectomy RT for each scenario. Consensus to omit RT was reached for cases with stage IIA and IIB disease with a pathological complete response or pathologically node negative. RT was instead suggested, also when a pathological complete response was reached after NAST, for stage IIIC disease and for all patients with initial stage IIB or IIIA, but pathologically node positive. Consensus favoring RT was also reached for triple-negative and HER2-positive cases. However, areas of controversy remain: No consensus was reached for the scenario represented by a 40-year-old patient with initial stage IIB disease, residual high grade invasive cancer but pathologically negative nodes. As far as RT volumes are concerned, no consensus was reached on the appropriateness of treating the supraclavicular region (judged as appropriate by a minority), whereas the inclusion of chest wall in the treated volume and the omission of a posterior axillary field reached a 100% consensus. A subgroup of patients aged more than 40, with clinical stage II disease, oestrogen receptor-positive subtype, obtaining pathological complete response or with 0–3 pathologically positive nodes without lymphovascular invasion or extracapsular extension was considered to have a less than 10% risk of locoregional failure also without postsurgical RT. Unfortunately, for this subgroup also the indications to NAST followed by mastectomy are relatively weaker. Factors favoring the indication to postmastectomy RT, apart from the advanced clinical and pathological stage, are instead young age, triple-negative receptor status, lymphovascular invasion, and extracapsular extension.

Future Efforts to Better Tailor Treatment to the Individual Patient

In the era of genomics, it is not surprising that biological factors are increasingly studied to define subsets of patients to be treated more aggressively. It has been suggested, for example, that test containing signatures for proliferation, such as the 21 gene recurrence score, can predict response to chemotherapy (9). The identification of genetic/biomolecular markers better defining the disease aggressiveness could also help to select cases requiring postoperative RT in properly studied perspective series. Meanwhile, it is possible to imagine that the response to neoadjuvant chemotherapy itself might be used to discriminate patients who will not need postoperative RT or more extended treated volumes. This is the subject, for example, of the NSABP B-51/RTOG 1304 clinical trial designed for patients who present with positive axillary nodes (fine needle aspiration or core needle biopsy) resulting histologically negative after chemotherapy: They will be randomized to receive or not postmastectomy chest wall and regional nodal RT or to receive postlumpectomy breast plus regional nodal RT versus breast RT only.

Conclusions

RT issues after NAST are partly unresolved. Some clear cut indications to postoperative RT after both BCS and mastectomy have been already defined. However, more studies should be conducted, exploring the prognostic and predictive efficacy of the different biological, genetic, pathological and clinical factors, to adequately define the clinical scenarios in which postoperative RT is really needed and the radiobiological and technical parameters of choice in the different subsets of patients.

References

1.
Mauri
D
Pavlidis
N
Ioannidis
JP
.
Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis
.
J Natl Cancer Inst
 .
2005
;
97
(
3
):
188
194
.
2.
Kaufmann
M
Karn
T
Ruckhäberle
E
.
Controversies concerning the use of neoadjuvant systemic therapy for primary breast cancer
.
World J Surg
 .
2012
;
36
(
7
):
1480
1485
.
3.
Mittendorf
EA
Buchholz
TA
Tucker
SL
et al
Impact of chemotherapy sequencing on local-regional failure risk in breast cancer patients undergoing breast-conserving therapy
.
Ann Surg
 .
2013
;
257
(
2
):
173
179
.
4.
Delpech
Y
Coutant
C
Hsu
L
et al
Clinical benefit from neoadjuvant chemotherapy in oestrogen receptor-positive invasive ductal and lobular carcinomas
.
Br J Cancer
 .
2013
;
108
(
2
):
285
291
.
5.
Smith
BL
.
Neoadjuvant versus adjuvant systemic therapy for operable breast cancer: equivalent outcomes?
Ann Surg
 .
2013
;
257
(
2
):
180
181
.
6.
Clarke
M
Collins
R
Darby
S
et al
;
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)
.
Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials
.
Lancet
 .
2005
;
366
(
9503
):
2087
2106
.
7.
Huang
EH
Tucker
SL
Strom
EA
et al
Postmastectomy radiation improves local-regional control and survival for selected patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and mastectomy
.
J Clin Oncol
 .
2004
;
22
(
23
):
4691
4699
.
8.
Fowble
BL
Einck
JP
Kim
DN
et al
;
Athena Breast Health Network
.
Role of postmastectomy radiation after neoadjuvant chemotherapy in stage II-III breast cancer
.
Int J Radiat Oncol Biol Phys
 .
2012
;
83
(
2
):
494
503
.
9.
Gianni
L
Zambetti
M
Clark
K
et al
Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer
.
J Clin Oncol
 .
2005
;
23
(
29
):
7265
7277
.