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Synchronous cancers are rarely detected when working-up a patient for a primary cancer. Neoadjuvant management of synchronous breast and pancreatic cancers, without a germline mutation, has yet to be discussed. Two patients were diagnosed with synchronous breast and pancreatic cancers at our institution over the last decade. A literature review was performed to evaluate the current evidence stance.
The first patient was 61-years old and diagnosed with a HER2+ breast cancer. The second patient was 77-years old and diagnosed with a Luminal B breast cancer. The inability to provide concurrent breast and pancreatic neoadjuvant therapy for the HER2+ patient, resulted in upfront surgery. The second patient was able to have both cancers treated simultaneously - neoadjuvant chemotherapy to the pancreas, and neoadjuvant endocrine therapy to the breast.
There is no single neoadjuvant regimen that treats both pancreatic and breast cancer. The differences in breast cancer sub-types impacted our neoadjuvant options. Our recent experience led us to the hypothesis that breast cancer care dictates treatment, while pancreatic cancer determines survival. There is a significant paucity in the literature regarding synchronous breast and pancreatic cancer.
The management of operable pancreatic cancer patients is complex and multifaceted. The typical pancreatic cancer presentation is late, with less than 20% up-front surgical candidates. The term “borderline” resectable has been used with varying definitions. The underpinning notion being that surgery is feasible, however the likelihood of incomplete resection is high (
The presence of synchronous pancreatic and breast cancers is rare, having been described in a handful of case reports, resulting in management difficulty (
BRCA1 and BRCA2 are associated with the DNA repair pathway and together, are the most common genetic cause for breast cancer, accounting for approximately 5% of all cases. Patients with BRCA1/2 mutations have a 72% and 69% lifetime risk of developing breast cancer respectively, with increased ovarian cancer risks. BRCA1 also increases the relative risk (RR) for pancreatic cancer by 2 to 4-fold, where BRCA2 increases RR by 3 to 8-fold (
The 5-year survival rate for breast cancer in Australia is approximately 91% (
However, our recent experience led us to the hypothesis that breast cancer care may dictate treatment, while pancreatic cancer determines survival. Here we present our two cases and review the current extent of literature for synchronous breast and pancreatic cancers.
From January 2020 until January 2021, two patients were diagnosed with synchronous pancreatic and breast cancers in the Upper Gastrointestinal Surgery Department of Royal North Shore Hospital, NSW, Australia, a tertiary referral centre for pancreatic cancer care. Ethical approval was obtained from the Northern Sydney Local Health District Human Research and Ethics Committee. Of the two patients, one underwent upfront surgery and the other received neoadjuvant chemotherapy. Given the rarity of synchronous pancreatic and breast cancer, a comprehensive literature review was performed. A literature search was performed using the PubMed, EMBASE, Medline, Web of Science, and Cochrane Library databases for studies published between 1 January 1990 and 31 August 2021. The following MeSH terms and their combinations were searched: (breast +/− cancer/neoplasm/tumor/tumour) and (pancreas/pancreatic +/− cancer/neoplasm/tumor/tumour) and (synchronous). Peer-reviewed papers with English abstracts were all reviewed. Two authors (AO & DK) independently reviewed the titles and abstracts to screen and extract relevant articles.
A 61-year-old woman presented with ongoing epigastric pain post cholecystectomy. An MRI scan identified an intraductal papillary mucinous neoplasm (IPMN). Due to significant patient anxiety and initial refusal for an endoscopic ultrasound (EUS), an FDG-PET was performed, identifying FDG uptake in a lesion in the pancreatic head, as well as a in a lesion in the left breast and two left axillary lymph nodes. An MRI scan of the breast noted a 37 mm irregular, spiculated lesion in the upper outer quadrant of the left breast. CNB of the breast lesion confirmed Grade 3 IDC, hormone receptors negative, amplified for HER-2, with a Ki67 of 40%. Axillary lymph node FNAB was positive for breast carcinoma. EUS of the pancreas identified a 1.5 cm mass in the neck of the pancreas and a lesion in the tail of the pancreas, with FNA confirming PDAC in both lesions. Full mutation search for BRCA1/2 and PALB2 were negative.
This case was discussed at both the Breast and Pancreas multi-disciplinary meetings, with the consensus recommendation made for up-front surgery with adjuvant chemotherapy. In this scenario, there were two aggressive malignancies with no significant overlap of active systemic treatments that would provide benefit in both cancers; therefore, the concern was for potential progression of one or both malignancies during a period of neoadjuvant systemic treatment, that would ultimately render one or both malignancies, inoperable.
The patient underwent an uneventful total pancreatectomy and simultaneous mastectomy and axillary nodal clearance. Histopathology confirmed two completely excised cancers - a Stage IIa pancreatic ductal adenocarcinoma with 1/29 lymph nodes, and a 19 mm breast cancer Grade 3 IDC with 23/25 positive axillary nodes. She was subsequently treated with Carboplatin, Paclitaxel and trastuzumab as adjuvant systemic treatment; this regimen was selected given evidence of activity in both malignancies for the chemotherapy component, with the trastuzumab directed towards the Her2-positive early breast cancer (EBC).
Unfortunately, a PET performed 5 months post operatively indicated pancreatic recurrence in the middle of the pancreatic bed, a poor prognostic indicator. She is currently undergoing chemotherapy with the FOLFIRINOX (oxaliplatin, irinotecan and 5-FU) regimen, with RT to the pancreatic bed, as salvage intent treatment.
The second patient was a 77-year-old woman, referred from her gastroenterologist after being investigated for weight loss, anorexia, and abdominal pain over 6 months. CT imaging identified an ill-defined hypodense mass at the junction of the body and neck of the pancreas with abnormally appearing lymph nodes, as well as left axillary lymphadenopathy. Breast ultrasound identified 2 lesions in the left breast, irregularly hypoechoic and in close proximity: 19 and 8 mm in size. CNB of the breast lesions confirmed Grade 2 IDC that was hormone receptor positive, HER-2 negative on IHC, with a Ki67 of 60%. The patient’s family history was unremarkable and genetic testing was negative for any known mutations.
The multi-disciplinary team recommended neoadjuvant chemotherapy directed towards the pancreatic malignancy with neo-adjuvant endocrine therapy for the breast cancer. She was commenced on the FOLFIRINOX chemotherapy regimen and Letrozole (an aromatase inhibitor, given her post-menopausal state).
She tolerated her chemotherapy regimen well. Her immediate post-chemotherapy PET-CT indicated resolution of FDG uptake in the breast and the axillary nodes, with reduction in FDG avidity to the pancreas. During her work up for operative intervention, she developed increasing Ca 19.9 levels, with a repeat PET-CT indicated liver metastases. Subsequently she was re-started on further chemotherapy and not deemed a surgical candidate.
We present here a series of two women presenting with synchronous operable breast and pancreatic malignancies, to a specialist multi-disciplinary quaternary referral centre. The management of these two cases differed, predominantly due to the breast pathology. In the first case, the inability to provide appropriate dual-spectrum neoadjuvant treatment (due to HER-2 amplification) resulted in up-front surgery. In the second case, due to the hormone receptor positivity, we were able to provide concurrent pancreatic-NACT and neoadjuvant endocrine treatment (NET) to the breast. Unsurprisingly, the outcomes of both cases were determined by the progression of the pancreatic adenocarcinoma, which is typically the more aggressive of the two tumour types.
After a comprehensive review of the literature, only 6 studies were found to have discussed synchronous pancreatic and breast cancer (
Summary of 6 papers discussing synchronous breast and pancreatic cancers.
| Authors, Year | Case | Breast Cancer | Pancreatic cancer | Treatment | Outcome |
|---|---|---|---|---|---|
| Nakanishi et al ( |
78y female - synchronous left breast cancer and pancreatic cancer | 48 mm IDC, with nodal involvement, NFI (T2N1M0) | 30 mm borderline resectable pancreatic body adenocarcinoma |
NAC: gemcitabine and nab-paclitaxel. Stable breast cancer and partial response to pancreatic cancer Pancreatosplenectomy with portal vein and gastroduodenal artery resection and reconstruction + left mastectomy with axillary lymph node dissection Flurouracil, epirubicin and cyclophosphamide |
No recurrence noted |
| Takada et al ( |
67y male - synchronous left breast and pancreatic cancer (with liver and peritoneal metastases) | 28 mm, IDC, TNBC (T2N0M0) | 40 mm unresectable pancreatic tail cancer |
Palliation due to hepatic failure secondary to pancreatic tumour growth |
Died |
| Castro et al ( |
41y female - synchronous locally advanced left breast cancer and pancreatic cancer, BRCA2 mutation | 75 mm Grade 2 IDC (ER/PR+, HER2-) with HG-DCIS, 8/23 LN (T3N2aM0) | 26 mm resectable pancreatic tail adenocarcinoma |
Left modified radical mastectomy Laparoscopic, hand assisted splenectomy, distal pancreatectomy, lymphadenectomy and bilateral salpingo-oophorectomy Adjuvant chemotherapy: doxorubicin-cisplatin followed by gemcitabine-NAB paclitaxel Radiotherapy (post-mastectomy and upper abdominal) + aromatase inhibitor For consideration of Olaparib therapy |
Alive at time of publication |
| Kim et al ( |
73y female - synchronous left breast cancer, pancreatic cancer, papillary carcinoma of the thyroid and GIST. | Multiple IDC, NFI (TxNxMx) | 18 mm unresectable pancreatic body adenocarcinoma with ductal dilatation and coealic axis invasion |
Patient refused aggressive treatment including surgery Agreed for treatment of the breast cancer and GIST (hormone therapy and chemotherapy): Letrozole + imatinib Supportive treatment for thyroid and pancreatic cancer |
Died 8 months after diagnosis |
| Unek et al ( |
50y male - synchronous right breast cancer and pancreatic cancer. |
11 mm Grade 1 IDC, ER+, PR-, HER2-, LVI+ (T4bNxM0) | 25 mm resectable pancreatic head adenocarcinoma |
Surgery: Whipple procedure and right mastectomy Radiotherapy + Chemotherapy
- Radiotherapy: to pancreatic region and chest wall - Chemotherapy: 5-Fu + Gemcitabine. Patient refused after 6 cycles due to metastatic spread
|
Died 10 months after diagnosis |
| Morganti et al ( |
69y male - 2 primary right breast cancers and primary pancreatic cancer with liver metastasis |
25 mm + 15 mm Grade 2 IDC, 0/25 LN (T2N0M0) | 30 mm unresectable pancreatic body and tail adenocarcinoma with vascular invasion with liver metastases |
Total right mastectomy Chemotherapy: carboplatin-taxotere, 15 cycles Zolidronic acid, monthly, 8 cycles LHRH for prostate cancer continued Chemotherapy second regimen due to disease progression: gemcitabine and oxaliplatin Worsening ascitic effusion with pain, dyspnoea and haematologic toxicity. Regimen changed to gemcitabine alone |
Died 17 months after diagnosis |
Of the available literature, only one case discussed NACT. This was in the regimen of gemcitabine and nab-paclitaxel. Adjuvant chemotherapy varied in the other 3 cases; doxorubicin-cisplatin followed by gemcitabine-NAB paclitaxel, 5-Fu and Gemcitabine, and carboplatin-taxotere. There was no discussion regarding the decision making behind any of the chemotherapy regimens in any of the papers.
At our institution, the default pancreatic cancer management sequence is neoadjuvant chemotherapy followed by surgery for tumours >2 cm and/or node positive. Current international guidelines are varied regarding this stance. The National Comprehensive Cancer Network (NCCN) suggest NACT usage in high-risk potentially resectable (borderline) tumours, however the American Society of Clinical Oncology (ASCO) guidelines suggest against NACT if tumours are potentially resectable (
There are currently multiple indications for neoadjuvant breast cancer treatment– ranging from receptor status, tumour size, nodal involvement, as well as desire to perform breast conservation therapy (
Our preferred chemotherapy regimen in pancreatic cancer is FOLFIRINOX, or a modified FOLFIRINOX, dependent on a patient’s European Cooperative Oncology Group (ECOG) performance status. The preference for FOLFIRINOX over Gemcitabine ± capecitabine is based off adjuvant studies that have shown superior survival rates for FOLFIRINOX compared to Gemcitabine, and from neoadjuvant FOLFIRINOX studies showing higher rates of R0 resections and favourable median overall survival (
Current breast cancer NACT typically involves a regimen containing an anthracycline and taxane (
For hormone receptor positive patients, neoadjuvant endocrine therapy (NET) has shown similar response rates, and rates of BCT, compared to NACT in post-menopausal women, with less side effects (
In HER-2 breast cancer patients ≥ T1c, NACT is recommended with sequential trastuzumab. In our patient the delivery of NACT with HER-2 directed therapy, typically AC-T and Trastuzumab, was inappropriate due to the lack of pancreatic treatment. The inability to treat the pancreatic and breast malignancy concurrently resulted in the necessity for upfront surgery. Trastuzumab can be delivered with FOLFIRINOX, as in HER2+ gastric cancers, however FOLFIRINOX has not shown any efficacy in breast cancer. Synchronous pancreatic and breast cancers, though rare, has had literature identifying breast cancer progression whilst on FOLFIRINOX for metastatic pancreatic cancer (
Directed HER-2 therapy alone is not appropriate, as shown in the KRISTINE trial (
Directed management of HR-positive, HER2-negative early breast cancer, relies on anti-estrogen therapy. In advanced HR-positive, HER2-negative breast cancers, the addition of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors has become the new standard of care. Their usage in EBC though has had mixed results (
The neoMONARCH phase 2 study compared two-week usage of Abemaciclib alone, Anastrozole alone or Abemaciclib and Anastrozole, in post-menopausal women in the neoadjuvant setting. The primary end point, Ki67 expression change, was elevated in treatment arms including Abemaciclib (Abemaciclib alone 91%, Abemaciclib and Anastrozole 93%, Anastrozole alone 63%). A complete pathological response (pCR) was achieved in 4% of the cohort that received Abemaciclib and Anastrozole. Further neoadjuvant studies are required however the potential addition of Abemaciclib to ET and would improve our management options in synchronous cancer patients.
The combination of Gemcitabine plus nanoparticle albumin-bound (nab)-Paclitaxel (GA) have been evaluated as first line regimens for both metastatic pancreatic adenocarcinoma and breast cancer. In both cancer sub-sets, the efficacy of the combination chemotherapy has been proven. However, they are not indicated as first line treatments in either cancer.
In pancreatic adenocarcinoma, a case series compared 485 consecutive patients receiving either FOLFIRINOX or GA as first line treatment (
Gemcitabine has limited use in the metastatic breast cancer setting. The current indication for its use (Gemcitabine and carboplatin) is relegated to patients who have already had first line treatment (anthracycline and taxane), or to those for whom there is a contraindication to an anthracycline and/or taxane only (
Synchronous breast and pancreatic breast cancers are rare, with literature limited to case reports only currently. Neoadjuvant therapy in both cancers, has resulted in significant improvements in the outcomes for patients in each individual cancer. However, there is no single neoadjuvant regimen that is shown to completely manage both. From our experience, we have noted that the typically less aggressive of the two cancers, the breast cancer, can direct our management due to the wider scope of treatment. In Luminal breast cancers, we can provide NET concurrently with our pancreatic chemotherapy regimen. However, in HER2+ or TNBC, the inability to provide any concurrent treatment to the breast results in our requirement of upfront surgery. Given how rapidly breast cancer management is evolving, we hope that further biologic treatments would wide our treatment options even greater in these complex synchronous cancer situations. However, given the paucity of the data, further research is required to determine whether the breast pathology, rather than pancreatic, should direct treatment.
The datasets presented in this article are not readily available because The data is not anonymized given the 2 complex cases. Requests to access the datasets should be directed to Adam Ofri, adamofri@gmail.com.
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Entire paper - AO, CD, AM Patient information and discussion - AS, MW, SS, JS, AG. All authors contributed to the article and approved the submitted version.
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